REVIEW published: 27 June 2022 doi: 10.3389/fimmu.2022.904686 The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection Esther Moga 1*, Elionor Lynton-Pons 1 and Pere Domingo 2 1Department of Immunology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Unidad de enfermedades infecciosas, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic Edited by: Penghua Wang, lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ University of Connecticut Health T follicular helper (Tfh), which play a critical role in infection control as well as long-term Center, United States protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes Reviewed by: Emily S. J. Edwards, interrupt viral replication by secreting antiviral cytokines (IFN-g and TNF-a) and directly Monash University, Australia killing infected cells, negatively correlating with stages of disease progression. In addition, Masaaki Miyazawa, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and Kindai University, Japan ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 *Correspondence: Esther Moga cases a dysregulated CD4+ T cell signature may contribute to the greater production of mmoga@santpau.cat pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components Specialty section: This article was submitted to revolve, since it orchestrates and leads antiviral response by regulating the inflammatory Viral Immunology, cascade and, as a consequence, the innate immune system, as well as promoting a a section of the journal Frontiers in Immunology correct humoral response through CD4+ Tfh cells. This review also analyses the critical Received: 25 March 2022 role of cellular immunity in modulating the development of high-affinity neutralizing Accepted: 27 May 2022 antibodies and germinal center B cell differentiation in memory and long-lived antibody Published: 27 June 2022 secreting cells. Finally, since there is currently a high percentage of vaccinated population Citation: and, in some cases, vaccine booster doses are even being administered in certain Moga E, Lynton-Pons E and Domingo P (2022) The Robustness of countries, we have also summarized newer approaches to long-lasting protective Cellular Immunity Determines the Fate immunity and the cross-protection of cellular immune response against SARS-CoV-2. of SARS-CoV-2 Infection. Front. Immunol. 13:904686. Keywords: SARS-CoV-2, cellular immunity, vaccine, COVID-19, helper T cells, cytotoxic T lymphocytes, doi: 10.3389/fimmu.2022.904686 severity, evasion Frontiers in Immunology | www.frontiersin.org 1 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity HIGHLIGHTS species of CoVs distributed in 27 subgenera, five genera, and two subfamilies (8, 9). HCoV are members of the Coronavirinae subfamily and are, in turn, categorized by the International . The presence of cross-reactivity, either humoral or cellular, Committee for the Taxonomy of Viruses into four major between common cold hCoV and SARS-CoV-2 does not genera: AlphaCoV, BetaCoV, GammaCoV, and DeltaCoV (9). prevent infection but may be associated with less severe The AlphaCoV genera contains the common cold-causing COVID-19. HCoV-229E and HCoV-NL63 HCoVs, whereas in the . The presence of SARS-CoV-2-specific CD4+ Th1 IFN-g- BetaCoV genera are placed the common cold-causing HCoV- producing cells and CD8+ CTLs cells were associated with HKU1 and HCoV-OC43, as well as SARS-CoV, and MERS-CoV reduced disease severity. (10). SARS-CoV-2 sequence analysis has demonstrated a distant . T lymphocyte recruitment to infected lung tissues and T similarity of 79% to SARS-CoV and a 50% similarity to MERS- lymphocyte apoptosis/necrosis caused by the cytokine CoV with an 88% sequence identity to bat-SL-CoVZC45, bat- storm might be crucial determinants of CD4+ and CD8+ SLCoVZXC21 and bat-derived SARS-like CoV (11, 12). T-cell lymphopenia in severe COVID-19 cases. The emergence of numerous SARS-CoV-2 variants of interest . Severe/fatal disease presents with excessive hyperactivation of (VOI) and variants of concern (VOC) is one of the most immune function with increased Tregs and Th2 and/or Th17 important developments in the COVID-19 pandemic (13). The cell-biased phenotype, leading to T cell exhaustion and most important VOC variants reported to date are Alpha subsequently to a state of anergy. (B.1.1.7), Beta (B.1.351), Gamma (P.1) (14, 15), Mu (B.1.621) . Functional memory B and T cells to SARS-CoV-2 have been (16), Delta (B.1.617.2) (17) and Omicron (B.1.1.529), with the detected 12 months after natural infection. SARS-CoV-2- latest VOC reported in November 2021 (18). Understanding the specific T cell memory may be long lasting given that impact of these variants on cellular immunity, in the context of COVID-19 convalescent patients develop SARS-CoV-2- COVID-19 infection and vaccination, is important for the specific TSCM cells that display a non-exhausted phenotype. development of effective strategies against future SARS-CoV- 2 variants. . The immunogenicity of SARS-CoV-2 vaccines involves the humoral response (number of spike-specific antibodies, neutralizing antibodies, and antibody neutralization capacity) and the cellular response (IFN-g-producing CD4+ VIRAL INFECTIONS AND T CELL and CD8+ T cells). Therefore, a combined analysis of IMMUNE RESPONSES humoral and cellular immunity is necessary for the identification of vaccine responders and the immune A harmonized innate and adaptive immune response is crucial protection evolution. for the control and clearance of most viral infections. These two branches of the immune system collaborate to protect the body against infections. First, innate immunity includes evolutionarily primitive molecular and cellular mechanisms that recognize INTRODUCTION pathogens as common molecular patterns with the aim of preventing infection and quickly eliminating them. Second, the Coronaviruses (CoVs) are enveloped viruses containing non- adaptive immune system takes longer to act but is characterised segmented, single-stranded, positive-sense RNA genome whose by a much more accurate response, as T and B lymphocytes primarily hosts are vertebrates (1, 2). Human Corovaniruses undergo antigen-specific selection and proliferation. For many (HCoVs) have been responsible for significant health-related and primary virus infections, it typically takes 7-10 days to prime and economic costs worldwide for the last 20 years. The first time we expand adaptive T cell immune responses in order to control the received alarming information regarding HCoVs was with the virus (19). Virus specific T cells have been shown to be protective appearance of severe acute respiratory syndrome coronavirus against other viruses, like influenza (20), while heterologous (SARS-CoV) in Guangdong Province (China) in November 2002 immunity against diverse influenza strains is associated with (3). By 2003, it had turned into a global infection with a mortality conserved memory T-cell epitopes (21–23). rate of 10% (4). The second HCoV outbreak occurred a decade later, in June 2012, with the Middle East respitatory syndrome Coronaviruses and Immunity: coronavirus (MERS-CoV), which originated in Jeddah, Saudi Previous Knowledge Arabia (5). In the case of MERS-CoV, a 35% fatality rate was The innate immune system includes physical and chemical reported worldwide (6). Finally, the current pandemic, which is barriers to infection, as well as the germline-encoded receptors, caused by severe acute respiratory syndrome coronavirus 2 known as pattern recognition receptors (PRRs), which recognise (SARS-CoV-2), originated in Wuhan, China in December 2019 the common molecular structures of many pathogens. PRRs bind and causes the infection designated COVID-19 (Coronavirus to pathogen-associated molecular patterns (PAMPs) and Disease 2019) (7). damage-associated molecular patterns (DAMPs) and trigger CoVs are classified in the realm Riboviria, order Nidovirales, cellular responses. As we know from other CoVs, double- suborder Cornidovirineae and family Coronaviridae with all 39 stranded RNA (dsRNA), which is a by-product of viral Frontiers in Immunology | www.frontiersin.org 2 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity genome replication and transcription, is a relevant PAMP model IFN-g and induce delayed-type hypersensitivity (DTH) fast at for CoVs (24, 25). It can be detected in the endosome by Toll-like antigen reencounter (48). Overall, T cell responses have been receptor 3 (TLR3) and in the cytoplasm by RNA helicases observed to have enhanced durability relative to antibody r e t i no i c a c i d - in d u c i b l e g e n e I (R I G- I ), m e l a no m a responses in SARS-CoV and MERS-CoV, hence it seems differentiation-associated protein 5 (MDA5), and protein cellular response is crucial for the longevity of the immunity kinase R (PKR) (26–28). Single-stranded RNA (ssRNA) can conferred by infection with CoVs. also be detected in the endosome by Toll-like receptor 7 (TLR7) (29). Altogether, this allows for the detection of viral Pre-Existing Immune Reactivity infection, activating signalling cascades like myeloid At the beginning of the pandemic outbreak, many studies differentiation primary response 88 (MyD88) and inducing the focused on the possibility of pre-existing immunity against production of type I interferons (IFNs) and nuclear factor kappa SARS-CoV-2. Considering that more than 90% of the human B (NF-kB) activation which, in turn, will induce the transcription population is seropositive for at least one out of three of the of pro-inflammatory cytokines (30). Collectively, this triggers an common cold-causing HCoVs (52), it is reasonable to antiviral immune response that constraints viral replication in hypothesize that there may be a degree of cross-reactivity infected and neighbouring cells. between the immunity conferred against common cold HCoVs However, CoVs are able to evade the mechanisms of innate and immunity against SARS-CoV-2. Among unexposed donors, immune detection, thereby preventing the generation of a proper 20% to 50% had lymphocytes exhibiting significant reactivity to immune response against viral infection (31). For example, the antigen peptide pools of SARS-CoV-2 (53–57). non-structural protein 3 (NSP3) of previous HCoVs has a Multiple investigations into early serological response to papain-like protease domain that inhibits the activation of IFN SARS-CoV-2 reported unconventional seroconversion patterns regulatory factor 3 (IRF3) and the ubiquitination of TANK- resembling those of secondary immune responses. During a binding kinase (TBK1), and RIG-I (32–35). Another example is secondary immune response, memory lymphocytes provide the the capacity of both SARS-CoV and MERS-CoV to prompt the necessary mechanisms for rapid, antigen-specific, effective production of double membrane vesicles lacking PRRs and their immune responses, and when the same pathogen infects the replication within them, thereby eluding the host viral dsRNA body a second time, it often originates only mild symptoms or detection system (36, 37). Furthermore, the SARS-CoV and may not cause any symptoms at all. A large serological study of MERS-CoV M protein has previously been shown to interact COVID-19 patients found IgM seroconversion before IgG with TNF receptor-associated factor 3 (TRAF3), disrupting (typical primary response), as expected in previously TRAF3-TBK1 association and thus suppressing type I IFN unexposed individuals, but also synchronous IgM and IgG, and production (38–40). IgM after IgG seroconversion, describing an uncommon pattern When the innate immune system is unable to control the viral of seroconversion to SARS-CoV-2 infection (58). In COVID-19 infection, the adaptive immune system assumes a very important convalescent subjects, IgG against the S protein of the HCoV- role. Previous studies of the adaptive immune response to earlier OC43 had higher titers than in unexposed subjects but that was CoVs reported that antibody response decreases rapidly after not true for the S protein of HCoV-229E, which suggests a more infection or immunization, especially in cases of mild or significant cross-reactivity between betacoronaviruses (59). The subclinical disease such as that caused by common cold CoVs same authors suggested that the early parallel production of IgM or mild MERS-CoVs, allowing for potential reinfection (41, 42). and IgG in response to SARS-CoV-2 infection might be Moreover, SARS-CoV and MERS-CoV have been shown to mediated by the stimulation of IgG memory B cells, as well as impair T cell function and induce T cell apoptosis (43, 44). by naïve B cells (59) indicating that the memory generated by Thus, a commonly observed phenotype during acute phase previous infections with other HCoVs would trigger a response disease in SARS-CoV and MERS-CoV patients, and also in to infection by the current SARS-CoV-2. COVID-19, was lymphopenia, which was seen particularly in However, although there are studies supporting the presence patients with severe disease (43, 45, 46). of pre-existing SARS-CoV-2 cross-reactive antibody neutralizing As is well known, the cytokine microenvironment generated capacity (60), others found no association between the presence by antigen presenting cells directs T cell phenotype of pre-existing cross-reactive antibodies to SARS-CoV-2 and differentiation and responses. Current evidence indicates that T protection against SARS-CoV-2 infections and hospitalizations helper 1 (Th1) response is crucial for the successful control of (61). That might be explained by the fact that those pre-existing SARS-CoV and MERS-CoV (47). cross-reactive antibodies share predominantly non-neutralizing There are a number of studies attempting to address the issue antibodies against the epitopes of previously circulating HCoVs of the immune memory persistence conferred by infection with (61–63). Assuming that shared cross-reactive antibodies to HCoVs. Some of those reveal that CD4+ and CD8+ memory T SARS-CoV-2 had no neutralizing activity, pre-existing cellular cell responses were identified in the blood of 70-100% of SARS- immunity would play a crucial protective role. CoV patients four and six years after infection (48–50) and (51) Several studies have provided evidence of the cross-reactivity even detected CD8+ T cell responses 11 years post-infection. of T cell responses between SARS-CoV-2 and the common cold These memory T cells may remain functionally active since HCoVs (55–57, 64–67). Mateus J. et al. (64) detected cross- another study revealed that they could proliferate, produce reactive CD4+ memory T cells with peptide pools selected on the Frontiers in Immunology | www.frontiersin.org 3 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity basis of homology between SARS-CoV-2 and other HCoVs and binding to translocase of outer mitochondrial membrane 70 concluded that memory CD4+ T cells recognizing common cold (TOM70) by ORF9b (74, 76, 81) and have suggested that ORF9b- HCoVs can exhibit substantial cross-reactivity to the TOM70 interaction may inhibit IFN-b promoter activity (82). homologous epitope in SARS-CoV-2. Cross-reactive CD8+ T Moreover, ORF9b expression by SARS-CoV-2 may prevent the cells also exist and, although they are less prevalent than cross- ubiquitination of NEMO (NF-kB essential modulator), NF-kB reactive CD4+ T cells (53), might be important determinants of activation and nuclear translocation (83). Furthermore, the immune protection at individual and population levels (68). ISGlyation (labelling with interferon-stimulated gene 15 (ISG15), Nevertheless, pre-existing T cell immunity to SARS-CoV-2 has an ubiquitin-like protein) of MDA5, which is required for apparently low avidity when compared to that developed following downstream pathway activation to lead to IFN-b secretion, may infection with SARS-CoV-2 and may not participate in immunity be inhibited by the NSP3 protein of SARS-CoV-2 (84). The NSP3 very effectively (69). Thus, the immunity developed by previous protein also seems to antagonize IRF3 stabilization (85). Other HCoVs is not sufficient to prevent subsequent infection by SARS- investigations have proposed that SARS-CoV-2-M protein CoV-2 but might be associated with less severe COVID-19 (70). antagonizes RLR signaling by inhibiting IFN-b and IFN-k gene Interestingly, there seems to be an inverse association expression and IFN-b promoter activity (86, 87). In addition, Xia H. between cross-reactive antibody levels and age as shown by et al. (88) demonstrated that M protein reduces ISRE (interferon- Shrwani K. et al. (63), who found children and younger people stimulated response element) reporter activity after treatment with to have higher pre-existing cross-reactive antibodies to SARS- IFN activation. SARS-CoV-2 has been also shown to inhibit the IFN CoV-2 than older individuals. In line with that finding, a signalling cascade at the signal transducer and activation of decrease in the magnitude and quality of SARS-CoV-2 cross- transcription (STATs) phosphorialtion level. For example, the reactive CD4+ T-cells response with age has also been reported expression inhibition and lysosomal degradation of interferon-a/b (71). Bearing this in mind, increased susceptibility to severe receptor 1 (IFNAR1) by NSP14 and ORF3a SARS-CoV-2 proteins COVID-19 in elderly patients may at least in part be explained by impairs STAT1 phosphorylation, as reported by Hayn M. et al. (89). a smaller pool of naïve T cells and the incapacity of the aged immune system to maintainthe SARS-CoV-2 cross-reactive T Adaptive Immune System Evasion cells induced by previous HCoV infection. All the above-mentioned strategies allow SARS-CoV-2 to overcome the first line of defense of the host and this is when the host’s second line of defense comes into play: the adaptive immune system. Unfortunately, SARS-CoV-2 has also developed SARS-COV-2 IMMUNE EVASION evasion mechanisms to overcome the adaptive immune system. Innate Immune System Evasion Humoral As mentioned above, the first line of defense provided by our A certain degree of SARS-CoV-2 antibody neutralization escape immune system against infection comes from the innate immune has been detected in every variant of concern: Alpha or B.1.1.7 system. SARS-CoV-2, like other viruses and other HCoVs, (90, 91), Beta or B.1.315 (92, 93), Gamma or P.1 (94, 95), Epsilon attempts to evade the innate immune system and has been encompassing the lineages B.1.427 and B.1.429 (96, 97), Delta or shown to do so by employing several different strategies. B.1.617.2 (17, 98), as well as Omicron or B.1.1.529 (99–101). As Apparently, the main tactic by which viruses manage to evade expected given the unprecedented high infection (and the innate immune system is the inhibition of type I IFN response at reinfection) rate numbers of the Omicron variant, this VOC different levels. It has been reported that SARS-CoV-2 may inhibit was able to easily evade past infection humoral immunity viral RNA recognition by modifying its own RNA and mimicking compared to the epidemiological surveillance data for Beta and host RNA. The non-structural proteins NSP13, NSP14 and NSP16 Delta variants (102). However, although the neutralization ability perform this function by mediating the addition of a 7- of convalescent sera against Omicron is low, a certain degree of methylguanyalte cap at the 5’ end of viral RNA in order to elude neutralization still exists, indicating that there is still a certain RIG-I and MDA5 recognition (72, 73). SARS-CoV-2 can also level of protective effect (102). Another relevant mechanism used inhibit type I IFN at different points of the signalling cascade, by SARS-CoV-2 to evade humoral response is the ability of this leading to IFN production after non-self nucleic acid detection. The virus to spread from cell to cell without exposure to the SARS-CoV-2 NSP15 protein may reduce IFN production as there is extracellular environment (103). This reduces the likelihood of evidence that NSP15 binds to NRDP1 (74), the E3 protein ubiquitin SARS-CoV-2 detection by SARS-CoV-2-specific antibodies and ligase, which is known to enhance TBK1 and IRF3 activation, therefore limits the role of humoral immunity in preventing viral thereby promoting IFN production (75). TBK1 activation can also spread within the host. be inhibited by the NSP13 SARS-CoV-2 protein (74, 76, 77), and is decreased, along with IRF3 activation, by open reading frame 9 Cellular (ORF9)- cyclic GMP−AMP synthase (cGAS)-stimulator of Notwithstanding these considerations regarding neutralization interferon genes (STING) interaction (78). The NSP12 SARS- escape, T-cell immunity against SARS-CoV-2 seems to be more CoV-2 protein seems to impair the nuclear translocation of IFR3 robust, since SARS-CoV-2-CD4+ and CD8+ T cell responses are by inhibiting IFN-b promoter activity (79, 80). Some studies have not substantially affected by the Alpha, Beta, Gamma and reported the disruption of RIG-I-like receptor (RLR) signalosome Epsilon variants of concern (B.1.429), likely because T cell Frontiers in Immunology | www.frontiersin.org 4 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity responses against SARS-CoV-2 are highly multi-antigenic and tends to elicit a higher peripheral blood T cell response with multi-specific, with many different epitopes being recognized by respect to asymptomatic infection (117, 118).The reduced CD4+ and CD8+ T cells in a given individual (55, 67, 104–106). frequencies of peripheral T cells during acute infection are Nonetheless, a T-cell response reduction to SARS-CoV-2 likely to be associated with decreased CD4+ T cell proliferation variants of concern Alpha, Beta, and Gamma (107) has been and CD8+ T cell hyperactivation with T cell migration into the demonstrated in vaccinated individuals and, as assessed in lungs (119). However, Liao L. et al. (120) have observed an COVID-19 convalescent patients and vaccinated individuals, increase of T cells in bronchoalveolar lavage fluids in mild two SARS-CoV-2-spike mutations in the Delta (B.1.617.2) and patients but not in severe patients, suggesting a difference in T the Delta plus (AY.2/B.1.617.2.2) may play a crucial role in HLA cell migration into the lungs in severe patients (120–122). recognition and in reducing cellular immune response (108). In Meanwhile, arguments supporting the role of cellular the case of vaccinated individuals, the above mentioned effect immunity in the control of primary SARS-CoV-2 infection may be due to the fact that the multi-specificity conferred by are supported by the fact that neutralizing antibody titers do natural SARS-CoV-2 infection cannot be achieved. Furthermore, not correlate with lessened disease severity in primary COVID- SARS-CoV-2 is able to reduce T-cell response through a 19 (123–125). Unlike neutralizing antibodies, SARS-CoV-2- mechanism mediated by infected monocytes. These can specific CD4+ and CD8+ T cells were found to be associated directly reduce T cell response and inhibit epithelial cell with reduced disease severity in the same individuals (124). In survival through the hypoxia inducible factor 1-alpha (HIF- agreement with these findings, there are reports of healthy 1a)/glycolysis-dependent axis, potentially contributing to individuals successfully controlling a SARS-CoV-2 infection immunopathology. This may explain why elevated glucose with little to no neutralizing (or receptor binding domain levels in diabetic individuals enhance viral replication and -RBD- IgG) antibodies detectable post-infection, while having cytokine expression in monocytes (109). significant SARS-CoV-2-specific T cell memory (67, 68, 124, Nevertheless, there are scarce studies investigating the T-cell 126). On the other hand, neutralizing antibody titers (and total immune escape of SARS-CoV-2 variants due to the difficulty of spike antibody titers) have indeed been positively correlated measuring T-cell response in clinical practice compared to with COVID-19 disease severity (58, 127–129), possibly antibody detection assays. More research needs to be indicating that under normal conditions the adaptive immune conducted on this issue in order to draw firmer conclusions. response works in strict balance, but when one arm becomes unbalanced the other tries to compensate. Thus, a defect in the cellular response would cause a greater humoral response to NATURAL INFECTION WITH SARS-COV-2 correct this deficiency. The role of cellular response has also (COVID-19) become evident in patients with agammaglobulinemia and no circulating B cells who have fully recovered from infection (130, In natural infection, when innate immunity stimulates the 131) and subjects with pharmaceutical depletion of B cells who adaptive response and sufficient effector T and B cells have resolved COVID-19 infection without requiring intensive care proliferated and differentiated, they work together to rapidly (132–136). Moreover, in patients with haematological and specifically eliminate infected cells and circulating virions. In malignancy, CD8+ T cells appear to compensate for the lack an orchestrated immune response, the humoral branch alone of humoral immunity and were associated with improved cannot clear an ongoing infection and a cellular immune outcomes, indicating a role for T cells in protection against response will also be necessary. Thus, the presence of both T SARS-CoV-2 infection (137). cells and antibodies is associated with the successful resolution of CD4+ T cell responses to pathogens are divided into three the average of cases of COVID-19 (53). T lymphocytes, the cells major types: Th1, Th2, and Th17. Th1 immune response, which is responsible for cell-mediated immunity, recognize the antigens characterized by T-bet-dependent responses and IFN-g secretion, present on antigen-presenting cells (APCs), and help phagocytes is generated against intracellular pathogens including viruses. In to destroy these microbes or to kill the infected cells. The best the Th1 response, pathogen clearance is mediated through effector defined T lymphocytes are helper and cytotoxic (or cytolytic) T cells including innate lymphoid cells 1 (ILC1), NK cells, and lymphocytes (CTLs), which present the cluster differentiation cytotoxic T lymphocytes (138–140). During SARS-CoV-2 acute markers CD4+ and CD8+, respectively. T cells also assist B infection, patients display a proliferation of IFN-g-producing Th1 lymphocytes to proliferate and differentiate into plasma cells that (IFN-g, IL-12, IL-15, IL-2 and TNF) cells and it has been suggested secrete different classes of antibodies. This process requires a that this Th1 cell-biased phenotype is associated with less severe fairly well-defined time frame. In SARS-CoV-2 infection, disease (54, 141). In patients with moderate disease, the core following an incubation period of four to seven days before COVID-19 inflammatory cytokine signature with IL-1a, IL-1b, IL- symptom onset, patients with COVID-19 progress towards 17A, and IFN-a observed in the first 10 days from symptom onset recovery after seven to 10 days or else develop serious illness declined steadily (142) and the same happens with the innate (110–112). The course of severe COVID-19 is characterised by cytokine IL-12, a key inducer of Th1 immune response, as well as an increased inflammatory response with a marked reduction in IFN-g (142). Early induction of IFN-g-secreting SARS-CoV-2- the number of T cells, frequently of both CD4+ and CD8+ T cells specific T cells with accelerated viral clearance is present in these (113–116). In addition, symptomatic SARS-CoV-2 infection patients with mild disease (125) Figure 1. Frontiers in Immunology | www.frontiersin.org 5 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity FIGURE 1 | Cellular immune response in Mild COVID-19. In mild COVID-19, there is an early induction of the Th1 cell-biased phenotype with IFN-g secreting SARS- CoV-2-specific T cells. In turn, SARS-CoV-2-specific CD8+ T cells perform rapid responses, acting as CTLs, secreting cytotoxic granules and high levels of IFN-g. Moreover, activated Tfh cells in the draining lymph nodes activate the naïve B cells that are necessary for the development of long-lived plasma cells and memory B cells. Cellular immune response in Severe COVID-19. During a severe course of COVID-19, there are reduced numbers and functions of DCs, leading to decreased numbers of CD4+ T cells. In this case, an elevation of Th2 phenotype and/or a dysregulation of the Treg/Th17 cell ratio toward the Th17 phenotype can be seen. Furthermore, decreased numbers of CD8+ T cells with an exhausted phenotype results in reduced CTL functionality while the T cell-mediated activation of B cells in extrafollicular focus induces their differentiation into short-lived plasma cells. The effector cells of CD8+ lineage are CTLs, whose major expansion, suggesting T cell migration to the infected site function is to eliminate cells harboring viruses. SARS-CoV-2 resulting in the overall peripheral counts (147). CD8+ T cells are specific for a range of SARS-CoV-2 antigens, The role of T folicular helper (Tfh) cells at germinal centers in and spike, nucleocapsid, M, and ORF3a proteins are well the development of a long-lasting, high-affinity antibody response represented (53, 56, 67, 126, 143, 144). CD8+ CTLs eliminate is well known (148, 149). In T cell-dependent immune responses, intracellular microbes mainly by killing infected cells by releasing T cells are important in the formation of an extrafollicular focus, in cytotoxic proteins stored within cytoplasmic granules to the which B cells proliferate and differentiate into plasma cells, most of target cell and subsequently triggering cellular apoptosis. In which are short-lived. The activation of T cells in the acute COVID-19, SARS-CoV-2-specific CD8+ T cells exhibit extrafollicular focus will cause some of them to develop into Tfh high levels of IFN-g, granzyme B, perforin, and CD107a cells and migrate into the germinal centers, where they perform molecules, some of which are present in the cytotoxic granules their functions, which are necessary for the development of both and are associated with potent cytotoxic effector functions (68, the bone marrow resident plasma cells and the memory B cells 124, 126, 145), developing fast CD8+ T cell responses (124). that enter in the recirculating lymphocyte pool (150, 151). Patients with milder disease and recovery have been associated Importantly, it appears that the germinal center reaction in with a more robust clonal expansion of CD8+ T cells in humans after vaccination persists over a longer period (152– peripheral blood (146). These findings would explain why, in 154). Evidence suggesting that the above described process is SARS-CoV-2 infections, the presence of virus-specific CD8+ T indeed what occurs following SARS-CoV-2 infection have been cells has been associated with better COVID-19 outcomes (124, provided by Mudd PA et al. (155) given that a high-magnitude, 144). Taken together, these observations suggest that cytotoxic SARS-CoV-2-specific CD4+ T cell response in the draining lymph activity is critical for the clearance of many viral infections and is nodes is present during the development of high-titer neutralizing therefore also important for the eradication of the infection antibody responses in the setting of COVID-19 mRNA reservoir. As with peripheral blood results, there is also an vaccination. The fact that CD4+ T cells in this type of response increase in SARS-CoV-2-specific CD8+ T cells in the provide help to B cells for the production of antibodies has been respiratory tract of moderate COVID-19, as demonstrated in demonstrated in other situations. For example, individuals with bronchoalveolar lavage fluid collected from COVID-19 patients. uncontrolled HIV and extremely low CD4+ T cell counts during Bronchoalveolar lavage fluid CD8+ T cells showed clonal vaccination lack seroconversion (156), and this has also been Frontiers in Immunology | www.frontiersin.org 6 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity observed in patients subjected to T cell-focused autopsy report, low levels of hyperactive T-cells in peripheral immunosuppressive regimens following solid organ blood and an accumulation of mononuclear cells in the lungs of transplantation who received a standard two-dose BNT162b2 the individual were observed (164). In addition, the high regimen (157). Overall, there is direct and indirect evidence of proportion of M/NP-specific CD8+ T cell responses compared the need for a robust T response for the generation of high-titer to the spike-specific CD4+ T cell response seen in mild disease is neutralizing antibody responses following COVID-19 infection or not found in severe disease (144). In fact, the percentages and mRNA vaccination. However, a lower quality and lack of absolute numbers of CD8+ T cells in severe disease were durability of humoral response has been observed during significantly reduced (163). This finding could suggest a natural SARS-CoV-2 infection. Thus, although there is evidence protective role of CD8+ T-cell response in mild disease or a of a robust T-cell-mediated activation of B cells in the non- pathogenic role of the CD4+ T-cell response in severe disease germinal-center, this may be due to a loss of germinal centers (144). The same applies in the case of ICU (intensive care unit) through a specific block of germinal center type B cell-lymphoma patients: total T-cell, CD4+ and CD8+ T-cell counts in peripheral 6 (Bcl-6)+ T follicular helper cell differentiation (158) Figure 1. blood were significantly lower than in non-ICU COVID-19 cases, This may compromise the early development of the high-affinity and the counts correlated negatively with patient survival (165). antibodies that could contribute to a certain attenuation of viral Some authors have observed an increased expression of the spread. Moreover, in COVID-19 patients, the relationship inhibitory receptor NKG2A, suggesting a decrease in CD8+ T between plasmablasts and activated Tfh is weak, even though cell functionality (160). NKG2A expression is upregulated on NK these individuals have a robust plasmablast response (114). At cells and CTLs in COVID-19 patients, with a decreased capacity to least part of the plasmablast response may be through activated produce CD107a, IFN-g, IL-2, granzyme B and TNF-a., which (CD38+HLA-DR+) CD4+ T cells, which might play a role in suggests functional exhaustion of cytotoxic lymphocytes in providing B cell help as a part of an extrafollicular response (114). COVID-19 patients (160). The upregulation of NKG2A expression may be a consequence of and to compensate for the hyperactivation of CD8+ T cells in the severe stage of COVID-19. Relation of Cellular Components With There is a cellular subset composed mainly of mucosal- Disease Severity associated invariant T (MAIT) cells, the CD161+ CD8+ T cells As mentioned above, an immune response properly coordinated which undergoes a strong reduction in frequency in individuals in time between the different components of innate and adaptive with severe COVID-19 (145). During viral infections, MAIT cells immunity is essential for it to be successful. In fact, if the adaptive can become activated and migrate to infection sites (166, 167). immune response starts too late, fatal COVID-19 develops, The sharp decline in circulating MAIT cells in severe COVID-19 defined as a situation in which the viral load is high (159). patients correlates with their presence in the airways of the IFN-g has already been discussed as a cytokine secreted by patients (168). The reduction of this population in peripheral CD4+ Th1 cells, but it is also secreted by differentiated CTLs. It blood is likely to be indicative of sequestration in the lungs, contributes to classical macrophage activation and inflammation potentially exacerbating tissue inflammation. in the host’s defense and in hypersensitivity reactions. It is likely During many acute viral infections, the period of peak T-cell that both CD4+ Th1 cells and CD8+ T cells contribute to the responses and plasmablast detection in peripheral blood is IFN-g–induced phagocytic clearance of ingested microbes. These relatively short (169–171). However, there is a subgroup of functions would explain the beneficial effect of rapid IFN-g COVID-19 disease patients with an over-aggressive immune secretion in response to an infectious process. Thus, Zheng M. response and/or a “cytokine storm” (172) due perhaps to a et al. (160) reported the secretion of IFN-g by both CD8+ T cells failure to regulate responses or a prolonged period of peak and CD4+ Th1 cells under conditions of severe COVID-19 immune responses because there is a stability over time of disease. Therefore, a poor T cell response contributes to SARS- CD8+ and CD4+ T-cell activation and plasmablast response CoV-2 viral persistence and COVID-19 mortality, whereas strong (114). There has been speculation on possible causes for the T cell responses are protective in the majority of individuals. As well-known cytopenia occurring in COVID-19. One of these seen in SARS-CoV-2 infection in non-human primate models, causes may be related to the recruitment of T cells to infected the deletion of CD8+ T cells impairs this protection (161).Thus, lung tissues to control viral infection (173). Another cause might human individuals with higher levels of IFN-g secreting T cells be the apoptosis or necrosis of T cells caused by the cytokine (measured by enzyme-linked immunosorbent spot assay) against storm that occurs in severe cases of COVID-19 (174). The severity the SARS-CoV-2 S protein, nuclear proteins, and membrane of the disease also correlates with cytokine levels and these proteins have a better protection against the virus (162), while a patients secrete higher levels of IL-6 and IL-10 (175). Thus, in CD4+ T cell IFN-g expression decrease has been reported in ICU patients a further increase in IL-6 and IL-10 plus TNF-a severe SARS-CoV-2 infection peripheral blood samples, and the (165) has been observed and has also been found to be higher in T cells of these patients seemed to be unable to produce IFN-g in the bronchoalveolar lavage fluid of deceased patients than in those response to viral proteins (163). who survive IL-6 (120). The increase in TNF-a may explain why Patients with severe COVID-19 have marked reductions in the antibody levels correlate with disease severity, since this cytokine number and frequency of both CD4+ and CD8+ T cells, but secreted by CD4+ T cells serves as a co-stimulatory signal for B increased activation of T cells (142, 145). Specifically, in an cells. Furthermore, the expansion of plasma cells in severe disease Frontiers in Immunology | www.frontiersin.org 7 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity has been associated with large and oligoclonal B cell Whether or not infection and hyperactivation persist, the expansions (145). immune system eventually enters an anergy state in which the The significant lymphopenia that COVID-19 patients present number of lymphocytes (including T and B lymphocytes), NK in the acute and severe phase is associated with a lower number cells and DCs continues decreasing in patients with a fatal and the functional impairment of dendritic cells (DCs), which are outcome. CD4+ T cell function is impaired, as evidenced by fundamental in T-cell antigenic presentation, compared to mild decreased activating receptors and an increased expression of patients (119, 145, 176), and those cells are significantly decreased CD45RA and CD28 (112). Thus, deceased patients have lower in fatal cases compared to survivors (177). Plasmacytoid DCs frequencies of HLA-DR+ and IFN-g-secreting cells within CD4+ (pDCs), which is responsible for the production of the type I IFNs and CD8+ T cells than survivors (186, 187). involved in virus defense, were also mainly reduced in abundance Another important factor to be taken into account during any and impaired in function in severe COVID-19 patients (145). In maintained immune response is a phenomenon called fact, during COVID-19 infection, the rapid loss of DCs numbers exhaustion, which is observed, for example, in some chronic and function may contribute to delayed T cell responses and the viral infections when CTL effector responses gradually extinguish features of low level IFN-I/IFN-III (178). over time (188). Exhausted cells express increased levels of This would partially explain the correlation of a fatal disease multiple inhibitory receptors, notably programmed cell death-1 course with the age of the patients since we should not forget the (PD-1), since the programmed cell death-ligand 1 (PD-L1)/PD-1 process known as “immunosenescence”, which features a immune checkpoint axis is the strongest T cell exhaustion reduction in the ability to fight novel infection (179) and a inducer, alongside cytotoxic T lymphocyte-associated protein 4 reduced abundance of DCs in elderly patients (180). Thus, the (CTLA-4), T cell immunoglobulin mucin-3 (TIM-3), presence of an immunosenescent phenotype, demonstrated by lymphocyte activation gene-3 (LAG-3), and others. It has been an elevated neutrophils-to-lymphocytes ratio, was found in reported that increased T cell exhaustion, observed by the high severe COVID-19 patients but not in mild disease (181). level expression of PD-1 and TIM-3 (165) induced by IL-10 Furthermore, patients with severe fatal disease up to 10 days (189) and decreased functional diversity correlates with the from the onset of symptoms have a excessive hyperactivation of degree of disease severity in patients with COVID-19 (190). In the immune function, demonstrated by significantly increased particular, Kreutmair S. et al. (191) showed that CD4+ T cells HLA-DR expression and IFN-g synthesis. In fact, a robust T cell increased PD-1 expression during the first days following response in critical patients may contribute to hyperreactivity and hospital admission and then normalized in moderate patients immunophatogenesis (182). Moreover, the proportion of T but remained elevated in severe disease (191). Likewise, as in regulatory (Treg) lymphocytes increases significantly in this memory CD4+ T cells, the frequency of PD-1 expressing cells phase, which negatively regulates immune response (112). As were reported to be higher after one month in recovered patients discussed previously, the Th1 cell-biased phenotype is associated with severe COVID-19, and correlated with the age of the patient with less severe disease (54, 141), but patients with SARS-CoV-2- (145). However, Rha M.S. et al. (192) reported that SARS-CoV- induced acute respiratory distress syndrome (ARDS) often tend to 2-specific CD8+ T cells expressing PD-1 were found not to be have a Th1:Th2 ratio weighted towards the Th2 type, leading to exhausted but functional. This is explained by the fact that PD-1 substantial lung tissue damage (183, 184). In addition, a broad is expressed on exhausted T cells but is also expressed on recently elevation of Th1, Th2 and Th17 signatures, including activated T cells (193–196) and the persistence of antigen inflammasome-dependent cytokines such as IL-1b, IL-18 and encounter results in the maintenance of PD-1 expression, Th2 and Th17 cytokines has been identified in patients with leading to exhausted T cells (197). PD-1 expression in the severe COVID-19 (142). Th2 and Th17 immunity depend on the peripheral blood of COVID-19 patients is also increased in the transcription factors GATA-3 and RORgt, respectively, and the exhaustion of other T cell subsets such as gd T, mucosa- predominant response is driven by (IL-4, IL-5, IL-13) and (IL-17, associated invariant T and invariant NKT cells which, in IL-22) respectively (138–140). Also, dysregulation of the Treg/ agreement with their exhausted phenotype, produce less IFN-g Th17 cell ratio toward the Th17 phenotype is an important than cells from healthy donors (168). Also, the T cells of ICU contributor to disease severity. IL-17 secreted during SARS- patients expressed increased PD-1 in bronchoalveolar lavage CoV-2 infection can promote migration of neutrophils and fluid as compared to peripheral blood T cells (198). monocytes into the pulmonary interstitium resulting in its Regarding ligand PD-L1, both soluble and membrane-bound consequent inflammation, as well as the activation of other PD-L1 increased levels are associated with the degree of severity cytokine cascades (G-CSF, TNFa, IL-1b and IL-6), which in COVID-19 (199–201). PD-L1/PD-1 overexpression in the contribute to aggravating this inflammation and tissue damage white adipose tissue of obese individuals during IFN-g secretion, (185). Thus, patients with severe COVID-19 showed a markedly which leads to the dysfunction of T cells and especially to a high number of CCR6+ Th17 cells in peripheral blood (164), even reduction in cytotoxic activity, explains why SARS-CoV-2 though not all patients with severe COVID-19 have increased IL- infection can worsen disease in obese individuals (202). 17 expression (163). These data suggest that the dysregulation of Overall, we can outline that T cells of COVID-19 patients Th polarization occurs in severe COVID-19 and a bias towards display a higher expression of PD-1 and that this elevated this type of Th response might define the disease course Figure 1. expression is correlated with disease severity, but whether or Frontiers in Immunology | www.frontiersin.org 8 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity not PD-1 expressing T cells in COVID-19 are functional needs to The other finding reported is the role that the sex of the patient be investigated further. To assess exhaustion, it will be important plays in the type of predominant immune response. It has been to take into account not only the expression of PD-1, but other shown that male patients have higher plasma levels of innate exhaustion markers and the time since a particular cell has immune cytokines, including IL-8 and IL-18, along with activated encountered the antigen in order to differentiate an exhausted non-classical monocytes. In contrast, female patients seem to cell from a recently activated cell. generate a more robust T cell activation during SARS-CoV-2 In the resolution of inflammation when the virus is eliminated, infection. A poor T cell response might be responsible for the both adaptive regulatory cells, such as regulatory T and B cells and worse outcomes observed in male patients, while in female patients, innate immune cells, such as macrophages and regulatory DCs, higher levels of cytokines related to innate immune response appear also contribute (203). In recovered patients, the number of to be associated with worse disease evolution (210). peripheral blood lymphocytes gradually increases (186, 187) A recently published study in mice suggests that specific T cell with a marked high frequency of spike specific CD4+ T cell and antibody responses develop independently of SARS-CoV-2 response (53, 126, 144), while the effector function of T cells is detection by some of the pattern recognition receptors (PRRs) of the not compromised (204). Two to four months after SARS-CoV-2 innate immunity system: TLR2-5 and TLR7, STING-cGAS, NLRP3 infection resolution, most of the components of cellular immunity (inflammasome activation), as well as RIP3 kinase (mediator of return to normality (204), though with significant increases in nedroptosis) and gasdermin D (mediator of pyroptosis). On the regulatory T cell frequencies and TIM-3 expression on CD4+ and other hand, these specific T cell responses, mainly featuring CD8+ T CD8+ T cells, while the cytotoxicity of T cells is significantly cells, are affected by the altered recognition of SARS-CoV-2 by the diminished (204). However, this immune response reversion is MDA5-IFNAR1 signalling pathways (211). Airway epithelial cells slower and the virus clearance time is prolonged in some critically from children appear to show an increased expression of MDA5 ill patients even after entering the recovery stage (112). compared to its expression level in SARS-CoV-2 positive adult epithelial cells (212). Consistent with this, we found several studies showing that children eliminate SARS-CoV-2 faster than adults, probably by detaining viral replication earlier (213–216). BALANCE BETWEEN INNATE AND In general terms, we have sought to emphasize that a balance ADAPTIVE IMMUNITY between the innate and the adaptive immune response is paramount for a favourable evolution and resolution of The first contact with pathogens is established by the host innate COVID-19 disease and its imbalance has detrimental immune system. It is noteworthy that the innate immune system is consequences, including the inability to configure a competent indeed capable of eliminating some infections on its own, adaptive response or the overactivation of the innate immune particularly when the infection is localized and caused by a low system which results in a cytokine storm. number of pathogens. But innate immunity is not sufficient to protect us fully from infectious diseases, in part because, as discussed earlier, many pathogens have features that allow them to evade innate immune responses. At this early stage, the innate IMMUNE MEMORY cytokine IL-12 has been shown to stimulate the differentiation of naive CD8+ T cells into effector CTLs and it is involved in the The balance between naïve and memory T cells is crucial for differentiation of CD4+ T cells into Th1 cells, both contributing to infection control. Naïve T cells are responsible for primary the IFN-g–induced phagocytic clearance of ingested microbes. infection response and memory T cells promote antigen- However, in some circumstances, the innate immune response specific immune responses, being able to protect the host from seeks to fill the gap left by the absence of a T cell response, re-infection with the same pathogen. Immune memory against attempting to assume t control of the immune response against the SARS-CoV-2 correlates positively with patient disease severity virus with an ever-expanding innate immunity activation. during acute phase infection, both in humoral and cellular Following this thread, there are many studies that have identified response (217). Thus, it has been shown that memory B cells innate cytokine/chemokine signatures of immunopathology (145, percentages among hospitalized cases were significantly higher 205–209). The most common observation in this line is an elevated than among non-hospitalized cases following infection (218). frequency of neutrophils in blood (145) and massive numbers of There are some studies that report relatively stable humoral neutrophils in the lungs, both of which are associated with severe, immunity for up to 6-12 moths post-infection (217–221) and end-stage COVID-19 disease (147, 206–208), as well as the Zhang J. et al. (217) described the detection of neutralizing cytokine storm (172). In severe COVID-19 patients, IL-12 and antibodies in convalescent COVID-19 patients even at 12 IFN-g increased over time; however, T cell depletion was detected months following symptoms onset. However, further studies in these patients and the remaining T cells did not produce larger show a clear decline of SARS-CoV-2 neutralizing antibodies in amounts of IFN-g (142). This suggests that the secretion of IFN-g the first months after infection (222–224), along with a by innate cells, such as ILCs and NK cells, or resident T cells in progressive decline in total antibody levels eight months after tissues were the primary contributors to the enhancement of the SARS-CoV-2 infection (218, 225). These inconsistencies in the IL-12 and IFN-g cytokine levels observed in severe patients. results of humoral immunity longevity may be due to variations Frontiers in Immunology | www.frontiersin.org 9 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity between the studied cohorts and the use of different techniques associated with disease severity with a bias towards TSCM in mild or distinct antibody-detection epitopes in the assays. disease and increased TEMRA in severe disease. In agreement with In a longitudinal study, Rodda L.B. et al. (226) detected previous studies that highlight the role of type I IFN in memory memory T cells, which secrete IFN-g and are able to clonally development (240), Adamo S. et al. (239) reported an expression expand following SARS-CoV-2-antigen re-exposure, at least enrichment of the genes involved in IFN signaling pathways in three months after disease onset. Further investigations have SARS-CoV2-specific memory CD8+ T cells. Thus, type I IFN detected maintained SARS-CoV-2-specific memory T cell signaling might be a key driver directing cells to become long- responses in COVID-19 convalescent patients at least 7-12 lived memory cells. While it has already been mentioned that months after infection (217, 221, 227) and this has been found TEMRA cells are associated with protection against viruses, it has to be true regardless of disease severity (227). Considering also been shown that they can accumulate during chronic viral immune memory at the tissue level, SARS-CoV-2-specific lung infections (241). In Long COVID syndrome, when compared to resident memory T cell can be detected at least 10 months COVID-19 convalescent individuals, an increase in CD8+ T following infection (228). Lung resident memory T cells may effector memory (T EM ) and CD8+ T EMRA cell number, be key players in limiting the severity of COVID-19 or the accompanied by a decrease in their functional activity, has potential for reinfection. In this regard, it has been described that been reported (242). a higher number of these resident memory T cells in the lungs The success of long-term memory T cells depends on the corresponds with a higher degree of clinical protection (229). generation of TSCM cells (243) since they have a higher self- Therefore, both B and T memory cells exhibit robust memory renewal ability and are multipotent cells, being able to response (225), indicating that, in the event of a re-encounter reconstitute several memory phenotypes (244). T cell memory with SARS-CoV-2, the levels of total and neutralizing antibodies developed during SARS-CoV-2 infection may be long-lasting and effector T cells necessary to respond efficiently to infection since COVID-19 convalescent patients develop SARS-CoV-2- might be rapidly recovered. In fact, B and T cell memory specific TSCM cells (192, 227, 239). Cohen K.W. et al. (245) functional responses to SARS-CoV-2 are still detectable 12 defined most SARS-CoV-2 CD4+ T cells as displaying a central months after natural infection (230). memory profile. Furthermore, Gurevich M. et al. (221) reported the presence of IL-2-secreting and IFN-g+IL-2-secreting SARS- Immune Memory Phenotypes CoV-2-specific central memory T cells that might be long-lasting Individuals who have undergone mild symptomatic SARS-CoV-2 memory phenotypes in accordance with previous studies (246). infection show, after a few months, an increase in circulating Th1 There are two different subsets of CCR7+ stem cell-like cytokine-producing CXCR5+ Tfh and CXCR5- non-Tfh cells, progenitors: CCR7+PD-1−TIGIT− cells are observed to display CD4+ CXCR3+ proliferative memory T cells and IFN-g- stem cell-like features, whereas CCR7+PD-1+TIGIT+ cells seem producing CD8+ T cells (226). In these mild COVID-19 cases, to exhibit exhausted traits (192, 247). SARS-CoV-2-specific TSCM CD8+ T memory cell responses predominate over CD4+ T cells rarely express PD-1 and TIGIT, making them non- memory cell responses and, additionally, the memory CD8+ T exhausted-like progenitors but functional memory T cells (227). cells specific for SARS-CoV-2 M and NP proteins exhibit the highest frequency of multiple cytokine production (144). Additionally, the SARS-CoV-2-specific memory CD4+ T cells VACCINATION of recovered individuals have the capacity to express CXCR5, ICOS, CD40L and proliferate at spike-protein re-exposure (226). A good adaptive immune response and immune memory are The expression of these markers and a variety of cytokines is vital to the success of vaccines and the achievement of a low important for T-B cells interaction (231) as they enable memory degree of reinfection. When studying natural immunity to the CD4+ T cells to help reactivate memory B cells and therefore start virus, including the role of SARS-CoV-2 specific T cells, it is producing antibodies against SARS-CoV-2 since, as discussed critical to fill in the current gaps in our knowledge for improved above, their levels may have decreased over time. This may serve vaccine design. The generation of a robust cellular immune to explain why, during the memory phase, an abundance of Tfh response is a desirable attribute for a vaccine against SARS- cells correlates with antibody response (232–234). CoV-2 because, as we have referred to throughout this report, Regarding the immune memory to SARS-CoV-2 in following natural infection, t T-cell response is activated rapidly convalescent individuals, a number of authors have underlined to control disease progression (53, 55, 144, 248), and these virus- the contribution of a subtype of terminally differentiated specific T-cell response have been shown to be associated with memory cells: the terminally differentiated effector memory T milder disease in COVID-19 patients (126). cells re-expressing marker CD45-RA (TEMRA). TEMRA have mRNA vaccination leads to the development of both humoral generally been associated with protection against viral infection and cellular immunity against the Covid-19 spike protein (249, (22, 235–238). During the memory phase following SARS-CoV-2 250) Figure 2. The onset of protection for mRNA vaccines has infection, a high prevalence (218, 227) and a progressive been observed as early as 10-12 days after the first dose (251) and enrichment of the TEMRA phenotype and T stem cell memory during this phase T cells and spike-specific antibodies are (TSCM) phenotype in SARS-CoV-2-specific CD8+ T cells (239) detectable (250, 252) but neutralizing antibodies do not appear has been described. The same authors postulate that the until after the second vaccine dose (253–256). In fact, the differentiation towards one phenotype or the other might be presence of anti-S reactive T cells secreting IFN-g or IL-2 is Frontiers in Immunology | www.frontiersin.org 10 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity level of IFN-g synthesis by the stimulated T-cells (264). In mice, the primary source of serum IFN-g one day after secondary immunization are CD4+ and CD8+ T cells, which results in improved myeloid cell activation after secondary immunization (211). Given all of the information mentioned above, the assessment of humoral immune response as determined by the measurement of antibodies against the receptor-binding domain of the spike protein after vaccination underestimates the immunogenicity of SARS-CoV-2 vaccines and a combined analysis of humoral and cellular immunity was proposed for the identification of vaccine responders (265). The type of response that vaccines should trigger must always be Th1 cell response or balanced T-cell responses, because when the response is Th2 cell, it has been associated with enhanced respiratory disease (266–270). Moreover, we have looked at how T cells also play a critical role in B-cell maturation and therefore the induction of a strong and durable antibody response (150). In FIGURE 2 | Parameters to be assessed regarding humoral and cellular most of the current COVID-19 vaccines that have reported response to SARS-CoV-2 mRNA vaccine. The top and middle figure outline clinical trial results, the induction of cellular response in the immunological response achieved after the first and second doses of humans has a Th1 bias and/or is characterized by IFN-g mRNA vaccines, respectively. The bottom figure summarizes the parameters expression and appears to be substantially protective against needed to assess protection against SARS-CoV-2. severe disease in all the major viral variants (271). Thus, in a longitudinal study, Painter M. M. et al. (250) show that mRNA remarkable as early as three days post-vaccination, but it is not vaccines induce Th1 and Tfh cell responses following the first until 14 days after completing the vaccination schedule that they dose, correlated with post-boost CD8+T cells and neutralizing reach their maximum levels (121). The development of humoral antibodies, respectively, which is expected since Th1 cells responses is gradual and they only consistently reach peak levels predominantly facilitate CD8+ T cell response, while Tfh cells after the second vaccination dose (257, 258). In fact, the highest help promote optimal B cell, germinal center, and antibody frequencies of spike-binding germinal centre B cells and responses (150, 272–274). At three months, 87% of vaccinated plasmablasts in draining lymph nodes were reached at twelve individuals developed either CD4+ or CD8+ T cell responses weeks after the second immunization (152). However, the (261) but after the first dose, in subjects who had no previous natural course of humoral immunity is to decrease over time, contact with SARS-CoV-2, vaccination induced rapid and robust with reductions in neutralizing antibody titers (259, 260). At SARS-CoV-2-specific CD4+ T cell responses compared with three months post-vaccination, the neutralization capacity was CD8+T cell responses, which developed gradually and were significantly decreased, in agreement with lower S-RBD antibody variable in magnitude (250). However, other authors observed levels (261) in all variants described to date, from Alpha to a robust, stable and fully functional response of Spike-specific Omicron (260). This may, feasibly, be due to the fact that not all CD8 T cells after primary vaccination (275). Differences in vaccine-induced plasmablasts commit or are maintained as long- cohort or methodology may have affected the discrepancy in lived memory plasma cells (123, 262, 263). However, these these findings, but these observations indicate that SARS-CoV-2- reductions do not necessarily correspond to proportional specific CD4+ T cells are largely contributors to the protection reductions in vaccine efficacy over time, and neither do observed early after the first vaccine dose (251, 276). reductions in vaccine efficacy against mild disease necessarily CD4+ T cell responses were detected after immunization with predict reductions in efficacy against severe disease. This may be ChAdOx-1 S, Ad26.COV2.S, mRNA-1273 or BNT162b2 because protection against severe disease is mediated not only by vaccines, and did not show significant differences between the antibody response, which might be relatively short lived for some different variants of concern, including the Omicron variant vaccines, but also by cell-mediated immunity and memory (143). One or two doses of vaccine elicited a persistent and responses, which are generally longer lived (152). In fact, robust cellular immune memory response even when vaccinated memory humoral and cellular responses are still detectable in individuals had been infected previously (277–279), with an vaccinated individuals who have not undergone COVID-19, and homogeneity in the magnitude (264). Although previous in those who have recovered from COVID-19, eight months after infected individuals had similar frequencies of vaccine-induced vaccination, despite a progressive decline in antibody levels CD4+ T cells as non-infected individuals, the former produced (230). At six months, although vaccinated individuals show a greater IFN-g following spike-stimulation (230) In addition, T decreased level of anti-S IgG, all of them present cell-mediated cell reactivity following vaccination or natural infection proved immune responses. The decrease in antibody titers is apparently to be similar across early strains (Alpha, Beta and Gamma) given compensated by an increased neutralization capacity and a that 93% and 97% of CD4 and CD8 epitopes are 100% conserved robust cellular immune response, which is reflected by a high across these variants, potentially reducing the severity of Frontiers in Immunology | www.frontiersin.org 11 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity COVID-19 if a progression of infection occurs, even though complemented by T cell responses, an alternative parallel neutralizing antibodies for emerging variants might be reduced strategy in vaccine generation should involve the inclusion of in comparison with the original strain of SARS-CoV-2 (280). additional antigens and T cell epitopes. This needs to be taken The same applies to the latest variants, since SARS-CoV-2 into account since early functional T cells specific to SARS-CoV- vaccination induces immunological CD4+ and CD8+ T cell 2- have a prognostic value with important implications for memory able to cross-recognize variants from Alpha to vaccine design and immune monitoring (125). Omicron (281). Furthermore, CD4+ and CD8+ SARS-CoV-2 spike-specific T cell responses triggered by prior infection with the original strain or BNT 162b2 vaccination, remain largely intact against the Omicron strain (282). This is due to the fact DISCUSSION that the vast majority of T cell epitopes are fully conserved (279– 281, 283–286), which suggests that the continued evolution of SARS-CoV-2, the coronavirus responsible for the last global variants has not been associated with increased viral escape from pandemic, which originated in December 2019, is the causative T cell responses at the population level, and HLA binding of the agent of the disease called COVID-19. The existence of cross- mutated epitopes has been well conserved for the majority of the reactivity between the immunity created by the common cold epitopes in Alpha to Omicron variants (281). Furthermore, it has coronaviruses and SARS-CoV-2 has not avoided infection but been proposed that the phenotype of memory and the helper may have possibly reduced the severity of the disease in some subset distribution of SARS-CoV-2-specific CD4+ and CD8+ T individuals. SARS-CoV-2, like other viruses, has evolved cells responses elicited by second dose vaccine are similar to the immune evasion mechanisms. In fact, multiple evasion ones detected in individuals who have gone through a natural mechanisms have been observed at the level of innate and SARS-CoV-2 infection (250). adaptive humoral immune response; however, the evasion The effect of the booster dose (a third vaccination dose) is mechanisms involved in cellular response, although existing, different in naïve individuals than in recovered COVID-19 require further study. individuals. In naïve individuals, this booster significantly SARS-CoV-2 infection triggers a potent immune response increased the levels of spike-specific antibodies and B and CD4+ that directs CD4+ T cellular adaptive response towards Th1 T cells, while in recovered COVID-19 individuals, the booster dose polarization and an activation of CD8+ CTLs, both IFN-g has minor effects (230), in line with what was observed for the producers, as well as an antibody-producing humoral response. second vaccine dose (249, 250). Moreover, the second vaccine dose Different mechanisms cause an imbalance in this response, in individuals who have undergone symptomatic infection with leading to an overactivation of the innate immune system and SARS-CoV-2 is associated with lower neutralizing antibody levels, resulting in a cytokine storm, together with a hyperactivation of in addition to T and B cell spike-specific frequencies, which the adaptive immune response that will consequently cause an suggests that a vaccine over-boost strategy may lead to anergy exhaustion of the latter. The fundamental role played by cellular and exhaustion (249, 257). It is important to differentiate between immunity as the main axis of the immune response against the immune response driven by the spike protein vaccine and the SARS-CoV-2, directing the different components involved, such response resulting from SARS-CoV-2 infection, where the innate as the innate response and the humoral response, is evidenced immune response triggers the adaptive immune response, and throughout this review. many more elements come into play in a much more complex Many efforts are being made during this pandemic to avoid process. In addition, the effect of repeated doses on overactivation both primoinfections and reinfections, using massive vaccination and the role played in its regulatory mechanisms, as well as the strategies. Both natural infection and vaccines produce long- appearance of exhausted cells, merits further study. term memory T cells, CD4+ and CD78+, which would protect Age is an important factor influencing vaccine responses, and the population particularly by avoiding severe infections and there have been studies that report elderly people responding being associated with a better prognosis. Even so, the immunity poorly to influenza, Hepatitis A and B, and pneumococcal vaccines provided by vaccination is more limited than the one provided as they develop lower antibody levels and weaker cell-mediated by natural infection. This is because the immune response in responses (287). Immunosenescense is likely to affect the vaccine vaccination is limited to the spike protein, which affects the response to SARS-CoV-2, as spike-specific IFN-g T cell responses variety of the T cell response and, notably, CD8+ T cell memory, to vaccines were impaired in the age group over 80 years (288, 289) which seems to be associated with a better prognosis in the case and individuals with a higher number of immunosenescent CD8+ of non-spike-specific CD8+ T cells. Thus, a future vaccination TEMRA cells have lower spike-specific CD4+ T cell responses (261). strategy should include antigens, which are also important for For example, a study of COVID-19-naïve nursing-home residents the cellular response, to fill in these gaps. found that both humoral and cellular responses declined after four A successful vaccination strategy requires knowledge of the weeks and remained lower than those of healthcare workers after previous immunity of the individual to SARS-CoV-2 since the 24 weeks (290). These data emphasize the need for additional cellular immune response to the vaccine is different in naïve measures for the fragile elderly population. individuals and in those who have been previously infected. In Considering this information, to ensure that responses the latter, there is a faster and more robust response, which is mediated by antibodies with neutralizing capacity are already detectable with the first vaccine dose. The different studies Frontiers in Immunology | www.frontiersin.org 12 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity TABLE 1 | Up-to-date key concepts to consider regarding natural infection or vaccination immunity against SARS-CoV-2. KEY CONCEPTS • The presence of cross-reactivity, either humoral or cellular, between common cold hCoV and SARS-CoV-2 does not prevent infection but may be associated with less severe COVID-19. • The presence of SARS-CoV-2-specific CD4+ Th1 IFN-g-producing cells and CD8+ CTLs cells were associated with reduced disease severity. • T lymphocyte recruitment to infected lung tissues and T lymphocyte apoptosis/necrosis caused by the cytokine storm might be crucial determinants of CD4+ and CD8+ T-cell lymphopenia in severe COVID-19 cases. • Severe /fatal disease presents with excessive hyperactivation of immune function with increased Tregs and Th2 and/or Th17 cell-biased phenotype, leading to T cell exhaustion and subsequently to a state of anergy. • Functional memory B and T cells to SARS-CoV-2 have been detected 12 months after natural infection. SARS-CoV-2-specific T cell memory may be long lasting given that COVID-19 convalescent patients develop SARS-CoV-2-specific TSCM cells that display a non-exhausted phenotype. • The immunogenicity of SARS-CoV-2 vaccines involves the humoral response (number of spike-specific antibodies, neutralizing antibodies, and antibody neutralization capacity) and the cellular response (IFN-g-producing CD4+ and CD8+ T cells). Therefore, a combined analysis of humoral and cellular immunity is necessary for the identification of vaccine responders and the immune protection evolution. performed to date make it possible to reach some conclusions writing of the manuscript and prepared the figures. PD concerning the role of cell-mediated immunity in SARS-CoV-2 contributed to the critical revision of the article for intellectual infection/vaccination (Table 1). Hopefully, in the future, the content and funding acquisition. All authors contributed to the analysis of cellular immunological memory generated by a article and approved the submitted version. previous infection or by vaccination will provide us with the tools required to fight against future variants of SARS-CoV-2 in terms of infection control, as well as future revaccination programs. FUNDING AUTHOR CONTRIBUTIONS This work was partially supported by the grant COV20/00070 (to PD), Instituto de Salud Carlos III, Madrid, Spain. PD is EM and EL-P contributed to the conception and design of the supported by a grant from the Programa de Intensificació n de article, the interpretation of the relevant literature, and the Investigadores (INT19/00036)-ISCIII. REFERENCES 9. Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, et al. The Species Severe Acute Respiratory Syndrome-Related Coronavirus: 1. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Classifying 2019-Ncov and Naming it SARS-CoV-2. Nat Microbiol (2020) 5 et al. A Phase 1/2 Study of Carfilzomib in Combination With Lenalidomide (4):536–44. doi: 10.1038/s41564-020-0695-z and Low-Dose Dexamethasone as a Frontline Treatment for Multiple 10. Woo PCY, Lau SKP, Lam CSF, Lau CCY, Tsang AKL, Lau JHN, et al. Myeloma. Blood (2012) 120(9):1801–9. doi: 10.1182/blood-2012-04-422683 Discovery of Seven Novel Mammalian and Avian Coronaviruses in the 2. Masters PS. The Molecular Biology of Coronaviruses. Adv Virus Res (2006) Genus Deltacoronavirus Supports Bat Coronaviruses as the Gene Source of 65:193–292. doi: 10.1016/S0065-3527(06)66005-3 Alphacoronavirus and Betacoronavirus and Avian Coronaviruses as the 3. Zhong NS, Zheng BJ, Li YM, Poon LLM, Xie ZH, Chan KH, et al. Gene Source of Gammacoronavirus and Deltacoronavi. J Virol (2012) 86 Epidemiology and Cause of Severe Acute Respiratory Syndrome (SARS) (7):3995–4008. doi: 10.1128/JVI.06540-11 in Guangdong, People’s Republic of China, in February, 2003. Lancet (2003) 11. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic Characterisation 362(9393):1353–8. doi: 10.1016/S0140-6736(03)14630-2 and Epidemiology of 2019 Novel Coronavirus: Implications for Virus 4. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, et al. A Major Origins and Receptor Binding. Lancet (2020) 395(10224):565–74. Outbreak of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J doi: 10.1016/S0140-6736(20)30251-8 Med (2003) 348(20):1986–94. doi: 10.1056/NEJMoa030685 12. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A Pneumonia 5. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier Outbreak Associated With a New Coronavirus of Probable Bat Origin. RAM. Isolation of a Novel Coronavirus From a Man With Pneumonia in Nature (2020) 579(7798):270–3. doi: 10.1038/s41586-020-2012-7 Saudi Arabia. N Engl J Med (2012) 367(19):1814–20. doi: 10.1056/ 13. Callaway E. Beyond Omicron: What’s Next for COVID’s Viral Evolution. NEJMoa1211721 Nature (2021) 600(7888):204–7. doi: 10.1038/d41586-021-03619-8 6. de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, et al. 14. Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison Middle East Respiratory Syndrome Coronavirus (MERS-CoV): EM, et al. SARS-CoV-2 Variants, Spike Mutations and Immune Escape. Announcement of the Coronavirus Study Group. J Virol (2013) 87 Nat Rev Microbiol (2021) 19(7):409–24. doi: 10.1038/s41579-021- (14):7790–2. doi: 10.1128/JVI.01244-13 00573-0 7. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus 15. Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 Variants of Concern in the From Patients With Pneumonia in China, 2019. N Engl J Med (2020) 382 United States-Challenges and Opportunities. JAMA - J Am Med Assoc (2021) (8):727–33. doi: 10.1056/NEJMoa2001017 325(11):1037–8. doi: 10.1001/jama.2021.2294 8. Siddell SG, Walker PJ, Lefkowitz EJ, Mushegian AR, Adams MJ, Dutilh BE, 16. Uriu K, Kimura I, Shirakawa K, Takaori-Kondo A, Nakada T, Kaneda A, et al. Additional Changes to Taxonomy Ratified in a Special Vote by the et al. Neutralization of the SARS-CoV-2 Mu Variant by Convalescent and International Committee on Taxonomy of Viruses (October 2018). Arch Vaccine Serum. N Engl J Med (2021) 385(25):2397–9. doi: 10.1056/ Virol (2019) 164(3):943–6. doi: 10.1007/s00705-018-04136-2 NEJMc2114706 Frontiers in Immunology | www.frontiersin.org 13 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 17. Mlcochova P, Kemp S, Dhar MS, Papa G, Meng B, Ferreira IATM, et al. 36. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, SARS-CoV-2 B.1.617.2 Delta Variant Replication and Immune Evasion. Limpens RWAL, et al. MERS-Coronavirus Replication Induces Severe In Nature (2021) 599:114–9. doi: 10.1038/s41586-021-03944-y Vitro Cytopathology and Is Strongly Inhibited by Cyclosporin A or 18. Karim SSA, Karim QA. Omicron SARS-CoV-2 Variant: A New Chapter in Interferon-a Treatment. J Gen Virol (2013) 94(PART8):1749–60. the COVID-19 Pandemic. Lancet (2021) 398(10317):2126–8. doi: 10.1016/ doi: 10.1099/vir.0.052910-0 S0140-6736(21)02758-6 37. Knoops K, Kikkert M, Van Den Worm SHE, Zevenhoven-Dobbe JC, van der 19. St. John AL, Rathore APS. Adaptive Immune Responses to Primary and Meer Y, Koster AJ, et al. SARS-Coronavirus Replication Is Supported by a Secondary Dengue Virus Infections. Nat Rev Immunol (2019) 19(4):218–30. Reticulovesicular Network of Modified Endoplasmic Reticulum. PLoS Biol doi: 10.1038/s41577-019-0123-x (2008) 6(9):1957–74. doi: 10.1371/journal.pbio.0060226 20. Hayward AC, Wang L, Goonetilleke N, Fragaszy EB, Bermingham A, Copas 38. Siu KL, Chan CP, Kok KH, Chiu-Yat Woo P, Jin DY. Suppression of Innate A, et al. Natural T Cell-Mediated Protection Against Seasonal and Pandemic Antiviral Response by Severe Acute Respiratory Syndrome Coronavirus M Influenza: Results of the Flu Watch Cohort Study. Am J Respir Crit Care Med Protein is Mediated Through the First Transmembrane Domain. Cell Mol (2015) 191(12):1422–31. doi: 10.1164/rccm.201411-1988OC Immunol (2014) 11(2):141–9. doi: 10.1038/cmi.2013.61 21. Greenbaum JA, Kotturi MF, Kim Y, Oseroff C, Vaughan K, Salimi N, et al. 39. Lui PY, Wong LYR, Fung CL, Siu KL, Yeung ML, Yuen KS, et al. Middle East Pre-Existing Immunity Against Swine-Origin H1N1 Influenza Viruses in the Respiratory Syndrome Coronavirus M Protein Suppresses Type I Interferon General Human Population. Proc Natl Acad Sci U S A (2009) 106 Expression Through the Inhibition of TBK1-Dependent Phosphorylation of (48):20365–70. doi: 10.1073/pnas.0911580106 IRF3. Emerg Microbes Infect (2016) 5(1):1–9. doi: 10.1038/emi.2016.33 22. Sridhar S, Begom S, Bermingham A, Hoschler K, Adamson W, Carman W, 40. Siu KL, Kok KH, Ng MHJ, Poon VKM, Yuen KY, Zheng BJ, et al. Severe Acute et al. Cellular Immune Correlates of Protection Against Symptomatic Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Pandemic Influenza. Nat Med (2013) 19(10):1305–12. doi: 10.1038/nm.3350 Production by Impeding Theformation of TRAF3·TANK·Tbk1/Ikkϵ 23. Wilkinson TM, Li CKF, Chui CSC, Huang AKY, Perkins M, Liebner JC, et al. Complex. J Biol Chem (2009) 284(24):16202–9. doi: 10.1074/jbc.M109.008227 Preexisting Influenza-Specific CD4 + T Cells Correlate With Disease 41. Drosten C, Meyer B, Müller MA, Corman VM, Al-Masri M, Hossain R, et al. Protection Against Influenza Challenge in Humans. Nat Med (2012) 18 Transmission of MERS-Coronavirus in Household Contacts. N Engl J Med (2):274–80. doi: 10.1038/nm.2612 (2014) 371(9):828–35. doi: 10.1056/NEJMoa1405858 24. Weber F, Wagner V, Rasmussen SB, Hartmann R, Paludan SR. Double- 42. Zhao J, Alshukairi AN, Baharoon SA, Ahmed WA, Bokhari AA, Nehdi AM, Stranded RNA Is Produced by Positive-Strand RNA Viruses and DNA et al. Recovery From the Middle East Respiratory Syndrome is Associated Viruses But Not in Detectable Amounts by Negative-Strand RNA Viruses. J With Antibody and T Cell Responses. Sci Immunol (2017) 2(14):eaan5393. Virol (2006) 80(10):5059–64. doi: 10.1128/JVI.80.10.5059-5064.2006 doi: 10.1126/sciimmunol.aan5393 25. Zielecki F, Weber M, Eickmann M, Spiegelberg L, Zaki AM, Matrosovich M, 43. Chu H, Zhou J, Wong BHY, Li C, Chan JFW, Cheng ZS, et al. Middle East et al. Human Cell Tropism and Innate Immune System Interactions of Respiratory Syndrome Coronavirus Efficiently Infects Human Primary T Human Respiratory Coronavirus EMC Compared to Those of Severe Acute Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways. Respiratory Syndrome Coronavirus. J Virol (2013) 87(9):5300–4. J Infect Dis (2016) 213(6):904–14. doi: 10.1093/infdis/jiv380 doi: 10.1128/JVI.03496-12 44. Yang Y, Xiong Z, Zhang S, Yan Y, Nguyen J, Ng B, et al. Bcl-xL Inhibits T- 26. Rasmussen SB, Reinert LS, Paludan SR. Innate Recognition of Intracellular Cell Apoptosis Induced by Expression of SARS Coronavirus E Protein in the Pathogens: Detection and Activation of the First Line of Defense. Apmis Absence of Growth Factors. Biochem J (2005) 392(1):135–43. doi: 10.1042/ (2009) 117(5–6):323–37. doi: 10.1111/j.1600-0463.2009.02456.x BJ20050698 27. Yim HCH, Williams BRG. Protein Kinase R and the Inflammasome. J Interf 45. Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ. Human Cytokine Res (2014) 34(6):447–54. doi: 10.1089/jir.2014.0008 Immunopathogenesis of Severe Acute Respiratory Syndrome (SARS). Virus 28. Yoneyama M, Jogi M, Onomoto K. Regulation of Antiviral Innate Immune Res (2008) 133(1):13–9. doi: 10.1016/j.virusres.2007.02.014 Signaling by Stress-Induced RNA Granules. J Biochem (2015) 159(3):279– 46. He Z, Zhao C, Dong Q, Zhuang H, Song S, Peng G, et al. Effects of Severe 86. doi: 10.1093/jb/mvv122 Acute Respiratory Syndrome (SARS) Coronavirus Infection on Peripheral 29. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, et al. Blood Lymphocytes and Their Subsets. Int J Infect Dis (2005) 9(6):323–30. Recognition of Single-Stranded RNA Viruses by Toll-Like Receptor 7. Proc doi: 10.1016/j.ijid.2004.07.014 Natl Acad Sci U S A (2004) 101(15):5598–603. doi: 10.1073/ 47. Li CK, Wu H, Yan H, Ma S, Wang L, Zhang M, et al. T Cell Responses to pnas.0400937101 Whole SARS Coronavirus in Humans. J Immunol (2008) 181(8):5490–500. 30. De Wit E, Van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: doi: 10.4049/jimmunol.181.8.5490 Recent Insights Into Emerging Coronaviruses. Nat Rev Microbiol (2016) 14 48. Fan YY, Huang ZT, Li L, Wu MH, Yu T, Koup RA, et al. Characterization of (8):523–34. doi: 10.1038/nrmicro.2016.81 SARS-CoV-Specific Memory T Cells From Recovered Individuals 4 Years 31. de Wilde AH, Snijder EJ, Kikkert M, van Hemert MJ. Host Factors in After Infection. Arch Virol (2009) 154(7):1093–9. doi: 10.1007/s00705-009- Coronavirus Replication. Curr Top Microbiol Immunol (2018) 419:1–42. 0409-6 doi: 10.1007/82_2017_25 49. Oh H-LJ, Chia A, Chang CXL, Leong HN, Ling KL, Grotenbreg GM, et al. 32. Ratia K, Kilianski A, Baez-Santos YM, Baker SC, Mesecar A. Structural Basis Engineering T Cells Specific for a Dominant Severe Acute Respiratory for the Ubiquitin-Linkage Specificity and Deisgylating Activity of SARS- Syndrome Coronavirus CD8 T Cell Epitope. J Virol (2011) 85(20):10464– CoV Papain-Like Protease. PLoS Pathog (2014) 10(5):e1004113. 71. doi: 10.1128/JVI.05039-11 doi: 10.1371/journal.ppat.1004113 50. Tang F, Quan Y, Xin Z-T, Wrammert J, Ma M-J, Lv H, et al. Lack of 33. Devaraj SG, Wang N, Chen Z, Chen Z, Tseng M, Barretto N, et al. Regulation Peripheral Memory B Cell Responses in Recovered Patients With Severe of IRF-3-Dependent Innate Immunity by the Papain-Like Protease Domain Acute Respiratory Syndrome: A Six-Year Follow-Up Study. J Immunol of the Severe Acute Respiratory Syndrome Coronavirus. J Biol Chem (2007) (2011) 186(12):7264–8. doi: 10.4049/jimmunol.0903490 282(44):32208–21. doi: 10.1074/jbc.M704870200 51. Ng OW, Chia A, Tan AT, Jadi RS, Leong HN, Bertoletti A, et al. Memory T 34. Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe Acute Cell Responses Targeting the SARS Coronavirus Persist Up to 11 Years Post- Respiratory Syndrome Coronavirus Papain-Like Protease Ubiquitin-Like Infection. Vaccine (2016) 34(17):2008–14. doi: 10.1016/ Domain and Catalytic Domain Regulate Antagonism of IRF3 and NF-kb j.vaccine.2016.02.063 Signaling. J Virol (2009) 83(13):6689–705. doi: 10.1128/JVI.02220-08 52. Gorse GJ, Patel GB, Vitale JN, O’Connor TZ. Prevalence of Antibodies to 35. Sun L, Xing Y, Chen X, Zheng Y, Yang Y, Nichols DB, et al. Coronavirus Four Human Coronaviruses is Lower in Nasal Secretions Than in Serum. Papain-Like Proteases Negatively Regulate Antiviral Innate Immune Clin Vaccine Immunol (2010) 17(12):1875–80. doi: 10.1128/CVI.00278-10 Response Through Disruption of STING-Mediated Signaling. PLoS One 53. Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, (2012) 7(2):e30802. doi: 10.1371/journal.pone.0030802 et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans Frontiers in Immunology | www.frontiersin.org 14 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity With COVID-19 Disease and Unexposed Individuals. Cell (2020) 181 72. Viswanathan T, Arya S, Chan SH, Qi S, Dai N, Misra A, et al. Structural Basis (7):1489–501.e15. doi: 10.1016/j.cell.2020.05.015 of RNA Cap Modification by SARS-CoV-2. Nat Commun (2020) 11(1):3718. 54. Weiskopf D, Schmitz KS, Raadsen MP, Grifoni A, Okba NMA, Endeman H, doi: 10.1038/s41467-020-17496-8 et al. Phenotype and Kinetics of SARS-CoV-2-Specific T Cells in COVID-19 73. Rosas-Lemus M, Minasov G, Shuvalova L, Inniss NL, Kiryukhina O, Patients With Acute Respiratory Distress Syndrome. Sci Immunol (2020) 5 Brunzelle J, et al. High-Resolution Structures of the SARS-CoV-2 2′-O- (48):eabd2071. doi: 10.1126/sciimmunol.abd2071 Methyltransferase Reveal Strategies for Structure-Based Inhibitor Design. Sci 55. Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, et al. SARS- Signal (2020) 13(651):eabe1202. doi: 10.1126/scisignal.abe1202 CoV-2-Reactive T Cells in Healthy Donors and Patients With COVID-19. 74. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A Nature (2020) 587(7833):270–4. doi: 10.1038/s41586-020-2598-9 SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug 56. Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, et al. Repurposing. Nature (2020) 583(7816):459–68. doi: 10.1038/s41586-020- SARS-CoV-2-Specific T Cell Immunity in Cases of COVID-19 and SARS, 2286-9 and Uninfected Controls. Nature (2020) 584(7821):457–62. doi: 10.1038/ 75. Wang C, Chen T, Zhang J, Yang M, Li N, Xu X, et al. The E3 Ubiquitin s41586-020-2550-z Ligase Nrdp1 “Preferentially” Promotes TLR-Mediated Production of Type I 57. Meckiff BJ, Ramı́rez-Suá stegui C, Fajardo V, Chee SJ, Kusnadi A, Simon H, Interferon. Nat Immunol (2009) 10(7):744–52. doi: 10.1038/ni.1742 et al. Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T 76. Gordon DE, Hiatt J, Bouhaddou M, Rezelj VV, Ulferts S, Braberg H, et al. Cells in COVID-19. Cell (2020) 183(5):1340–53.e16. doi: 10.1016/ Comparative Host-Coronavirus Protein Interaction Networks Reveal Pan- j.cell.2020.10.001 Viral Disease Mechanisms. Science (2020) 370(6521):eabe9403. doi: 10.1126/ 58. Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, et al. Antibody science.abe9403 Responses to SARS-CoV-2 in Patients With COVID-19. Nat Med (2020) 26 77. Vazquez C, Swanson SE, Negatu SG, Dittmar M, Miller J, Ramage HR, et al. (6):845–8. doi: 10.1038/s41591-020-0897-1 SARS-CoV-2 Viral Proteins NSP1 and NSP13 Inhibit Interferon Activation 59. Nguyen-Contant P, Embong AK, Kanagaiah P, Chaves FA, Yang H, Branche Through Distinct Mechanisms. PLoS One (2021) 16(6):e0253089. AR, et al. S Protein-Reactive IGG and Memory B Cell Production After doi: 10.1371/journal.pone.0253089 Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. 78. Han L, Zhuang MW, Deng J, Zheng Y, Zhang J, Nan ML, et al. SARS-CoV-2 MBio (2020) 11(5):1–11. doi: 10.1128/mBio.01991-20 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple 60. Ng KW, Faulkner N, Cornish GH, Rosa A, Harvey R, Hussain S, et al. Components of the RIG-I/MDA-5–MAVS, TLR3–TRIF, and cGAS– Preexisting and De Novo Humoral Immunity to SARS-CoV-2 in Humans. STING Signaling Pathways. J Med Virol (2021) 93(9):5376–89. Sci (80- ) (2020) 370(6522):1339–43. doi: 10.1126/science.abe1107 doi: 10.1002/jmv.27050 61. Anderson EM, Goodwin EC, Verma A, Arevalo CP, Bolton MJ, Weirick ME, 79. Lei X, Dong X, Ma R, Wang W, Xiao X, Tian Z, et al. Activation and Evasion et al. Seasonal Human Coronavirus Antibodies are Boosted Upon SARS- of Type I Interferon Responses by SARS-CoV-2. Nat Commun (2020) 11 CoV-2 Infection But Not Associated With Protection. Cell (2021) 184 (1):3810. doi: 10.1038/s41467-020-17665-9 (7):1858–64.e10. doi: 10.1016/j.cell.2021.02.010 80. Wang W, Zhou Z, Xiao X, Tian Z, Dong X, Wang C, et al. SARS-CoV-2 62. Poston D, Weisblum Y, Wise H, Templeton K, Jenks S, Hatziioannou T, Nsp12 Attenuates Type I Interferon Production by Inhibiting IRF3 Nuclear et al. Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Translocation. Cell Mol Immunol (2021) 18(4):945–53. doi: 10.1038/s41423- Neutralizing Activity in Prepandemic Sera From Individuals With Recent 020-00619-y Seasonal Coronavirus Infection. Clin Infect Dis (2021) 73(5):E1208–11. 81. Gao X, Zhu K, Qin B, Olieric V, Wang M, Cui S. Crystal Structure of SARS- doi: 10.1093/cid/ciaa1803 CoV-2 Orf9b in Complex With Human TOM70 Suggests Unusual Virus- 63. Shrwani K, Sharma R, Krishnan M, Jones T, Mayora-Neto M, Cantoni D, Host Interactions. Nat Commun (2021) 12(1):2843. doi: 10.1038/s41467- et al. Detection of Serum Cross-Reactive Antibodies and Memory Response 021-23118-8 to SARS-CoV-2 in Prepandemic and Post-COVID-19 Convalescent 82. Jiang HW, Zhang HN, Meng QF, Xie J, Li Y, Chen H, et al. SARS-CoV-2 Samples. J Infect Dis (2021) 224(8):1305–15. doi: 10.1093/infdis/jiab333 Orf9b Suppresses Type I Interferon Responses by Targeting TOM70. Cell 64. Mateus J, Grifoni A, Tarke A, Sidney J, Ramirez SI, Dan JM, et al. Selective Mol Immunol (2020) 17(9):998–1000. doi: 10.1038/s41423-020-0514-8 and Cross-Reactive SARS-CoV-2 T Cell Epitopes in Unexposed Humans. Sci 83. Wu J, Shi Y, Pan X, Wu S, Hou R, Zhang Y, et al. SARS-CoV-2 ORF9b (2020) 370(6512):89–94. doi: 10.1126/science.abd3871 Inhibits RIG-I-MAVS Antiviral Signaling by Interrupting K63-Linked 65. Sette A, Crotty S. Pre-Existing Immunity to SARS-CoV-2: The Knowns and Ubiquitination of NEMO. Cell Rep (2021) 34(7):108761. doi: 10.1016/ Unknowns. Nat Rev Immunol (2020) 20(8):457–8. doi: 10.1038/s41577-020- j.celrep.2021.108761 0389-z 84. Liu GQ, Lee JH, Parker ZM, Acharya D, Chiang JJ, van Gent M, et al. ISG15- 66. Saletti G, Gerlach T, Jansen JM, Molle A, Elbahesh H, Ludlow M, et al. Older Dependent Activation of the Sensor MDA5 is Antagonized by the SARS- Adults Lack SARS CoV-2 Cross-Reactive T Lymphocytes Directed to CoV-2 Papain-Like Protease to Evade Host Innate Immunity. Nat Microbiol Human Coronaviruses OC43 and NL63. Sci Rep (2020) 10(1):21447. (2021) 6(4):467–78. doi: 10.1038/s41564-021-00884-1 doi: 10.1038/s41598-020-78506-9 85. Moustaqil M, Ollivier E, Chiu HP, Van Tol S, Rudolffi-Soto P, Stevens C, 67. Nelde A, Bilich T, Heitmann JS, Maringer Y, Salih HR, Roerden M, et al. et al. SARS-CoV-2 Proteases PLpro and 3clpro Cleave IRF3 and Critical SARS-CoV-2-Derived Peptides Define Heterologous and COVID-19- Modulators of Inflammatory Pathways (NLRP12 and TAB1): Implications Induced T Cell Recognition. Nat Immunol (2021) 22(1):74–85. for Disease Presentation Across Species. Emerg Microbes Infect (2021) 10 doi: 10.1038/s41590-020-00808-x (1):178–95. doi: 10.1080/22221751.2020.1870414 68. Schulien I, Kemming J, Oberhardt V, Wild K, Seidel LM, Killmer S, et al. 86. Zheng Y, Zhuang MW, Han L, Zhang J, Nan ML, Zhan P, et al. Severe Acute Characterization of Pre-Existing and Induced SARS-CoV-2-Specific CD8+ Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) T Cells. Nat Med (2021) 27(1):78–85. doi: 10.1038/s41591-020-01143-2 Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/ 69. Bacher P, Rosati E, Esser D, Martini GR, Saggau C, Schiminsky E, et al. Low- MDA-5 Signaling. Signal Transduct Target Ther (2020) 5(1):299. Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals doi: 10.1038/s41392-020-00438-7 and Humans With Severe COVID-19. Immunity (2020) 53(6):1258–71.e5. 87. Fu YZ, Wang SY, Zheng ZQ, Huang Y, Li WW, Xu ZS, et al. SARS-CoV-2 doi: 10.1016/j.immuni.2020.11.016 Membrane Glycoprotein M Antagonizes the MAVS-Mediated Innate 70. Sagar M, Reifler K, Rossi M, Miller NS, Sinha P, White LF, et al. Recent Antiviral Response. Cell Mol Immunol (2021) 18(3):613–20. doi: 10.1038/ Endemic Coronavirus Infection is Associated With Less-Severe COVID-19. s41423-020-00571-x J Clin Invest (2021) 131(1):e143380. doi: 10.1172/JCI143380 88. Xia H, Cao Z, Xie X, Zhang X, Chen JYC, Wang H, et al. Evasion of Type I 71. Loyal L, Braun J, Henze L, Kruse B, Dingeldey M, Reimer U, et al. Cross- Interferon by SARS-CoV-2. Cell Rep (2020) 33(1):108234. doi: 10.1016/ Reactive CD4+ T Cells Enhance SARS-CoV-2 Immune Responses Upon j.celrep.2020.108234 Infection and Vaccination. Sci (80- ) (2021) 374(6564):eabh1823. 89. Hayn M, Hirschenberger M, Koepke L, Nchioua R, Straub JH, Klute S, et al. doi: 10.1126/science.abh1823 Systematic Functional Analysis of SARS-CoV-2 Proteins Uncovers Viral Frontiers in Immunology | www.frontiersin.org 15 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity Innate Immune Antagonists and Remaining Vulnerabilities. Cell Rep (2021) 107. Gallagher KME, Leick MB, Larson RC, Berger TR, Katsis K, Yam JY, et al. 35(7):109126. doi: 10.1016/j.celrep.2021.109126 MGH COVID-19 Collection & Processing Team, Maus MV. SARS -CoV-2 90. Collier DA, De Marco A, Ferreira IATM, Meng B, Datir R, Walls AC, et al. T-Cell Immunity to Variants of Concern Following Vaccination. bioRxiv SARS-CoV-2 B.1.1.7 Sensitivity to mRNA Vaccine-Elicited, Convalescent [Preprint] (2021) 3:2021.05.03.442455. doi: 10.1101/2021.05.03.442455 and Monoclonal Antibodies. medRxiv Prepr Serv Heal Sci (2021) 593:136– 108. Zhang H, Deng S, Ren L, Zheng P, Hu X, Jin T, et al. Profiling CD8+ T Cell 41. doi: 10.1038/s41586-021-03412-7 Epitopes of COVID-19 Convalescents Reveals Reduced Cellular Immune 91. Graham C, Seow J, Huettner I, Khan H, Kouphou N, Acors S, et al. Responses to SARS-CoV-2 Variants. Cell Rep (2021) 36(11):109708. Neutralization Potency of Monoclonal Antibodies Recognizing Dominant doi: 10.1016/j.celrep.2021.109708 and Subdominant Epitopes on SARS-CoV-2 Spike is Impacted by the B.1.1.7 109. Codo AC, Davanzo GG, de Brito Monteiro L, de Souza GF, Muraro SP, Variant. Immunity (2021) 54(6):1276–89.e6. doi: 10.1016/ Virgilio-da-Silva JV, et al. Elevated Glucose Levels Favor SARS-CoV-2 j.immuni.2021.03.023 Infection and Monocyte Response Through a HIF-1a/Glycolysis- 92. Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, Kgagudi P, Dependent Axis. Cell Metab (2020) 32(3):437–46.e5. doi: 10.2139/ Oosthuysen B, et al. SARS-CoV-2 501y.V2 Escapes Neutralization by ssrn.3606770 South African COVID-19 Donor Plasma. Nat Med (2021) 27(4):622–5. 110. ECDC. 2020 EC for DP and C (ECDC). Q & A on Novel Coronavirus. S. doi: 10.1038/s41591-021-01285-x European Centre for Disease Prevention and Control (ECDC). Q & A on 93. Li Q, Nie J, Wu J, Zhang L, Ding R, Wang H, et al. SARS-CoV-2 501y.V2 Novel Coronavirus. Stockholm: ECDC (2020). Available at: https://www. Variants Lack Higher Infectivity But do Have Immune Escape. Cell (2021) ecdc.europa.eu/en/covid-19/questions-answers. 184(9):2362–71.e9. doi: 10.1016/j.cell.2021.02.042 111. He W, Yi GY, Zhu Y. Estimation of the Basic Reproduction Number, 94. Wang P, Casner RG, Nair MS, Wang M, Yu J, Cerutti G, et al. Increased Average Incubation Time, Asymptomatic Infection Rate, and Case Fatality Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. Cell Host Rate for COVID-19: Meta-Analysis and Sensitivity Analysis. J Med Virol Microbe (2021) 29(5):747–51.e4. doi: 10.1016/j.chom.2021.04.007 (2020) 92(11):2543–50. doi: 10.1002/jmv.26041 95. Hoffmann M, Arora P, Groß R, Seidel A, Hörnich BF, Hahn AS, et al. SARS- 112. Zhou X, Ye Q. Cellular Immune Response to COVID-19 and Potential CoV-2 Variants B.1.351 and P.1 Escape From Neutralizing Antibodies. Cell Immune Modulators. Front Immunol (2021) 12. doi: 10.3389/ (2021) 184(9):2384–93.e12. doi: 10.1016/j.cell.2021.03.036 fimmu.2021.646333 96. Garcia-Beltran WF, Lam EC, St. Denis K, Nitido AD, Garcia ZH, Hauser 113. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical Features of BM, et al. Multiple SARS-CoV-2 Variants Escape Neutralization by Vaccine- Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet Induced Humoral Immunity. Cell (2021) 184(9):2372–83.e9. doi: 10.1016/ (2020) 395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5 j.cell.2021.03.013 114. Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, et al. 97. Deng X, Garcia-Knight MA, Khalid MM, Servellita V, Wang C, Morris MK, Deep Immune Profiling of COVID-19 Patients Reveals Distinct et al. Transmission, Infectivity, and Antibody Neutralization of an Emerging Immunotypes With Therapeutic Implications. Science (2020) 369(6508): SARS-CoV-2 Variant in California Carrying a L452R Spike Protein eabc8511. doi: 10.1126/science.abc8511 Mutation. medRxiv (2021) 9:2021.03.07.21252647. doi: 10.1101/ 115. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, 2021.03.07.21252647 Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in 98. Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel-Benhassine F, Rajah COVID-19 Patients With Severe Respiratory Failure. Cell Host Microbe MM, et al. Reduced Sensitivity of SARS-CoV-2 Variant Delta to Antibody (2020) 27(6):992–1000.e3. doi: 10.1016/j.chom.2020.04.009 Neutralization. Nature (2021) 596(7871):276–80. doi: 10.1038/s41586-021- 116. Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, et al. Heightened Innate 03777-9 Immune Responses in the Respiratory Tract of COVID-19 Patients. Cell Host 99. Schmidt F, Muecksch F, Weisblum Y, Da Silva J, Bednarski E, Cho A, et al. Microbe (2020) 27(6):883–90.e2. doi: 10.1016/j.chom.2020.04.017 Plasma Neutralization of the SARS-CoV-2 Omicron Variant. N Engl J Med 117. Reynolds CJ, Swadling L, Gibbons JM, Pade C, Jensen MP, Diniz MO, et al. (2022) 386(6):599–601. doi: 10.1056/NEJMc2119641 Discordant Neutralizing Antibody and T Cell Responses in Asymptomatic 100. Zou J, Xia H, Xie X, Kurhade C, Machado RRG, Weaver SC, et al. and Mild SARS-CoV-2 Infection. Sci Immunol (2020) 5(54):eabf3698. Neutralization Against Omicron SARS-CoV-2 From Previous non- doi: 10.1126/sciimmunol.abf3698 Omicron Infection. Cell Host Microbe (2022) 30(4):485–8.e3. doi: 10.1038/ 118. Zuo J, Dowell AC, Pearce H, Verma K, Long HM, Begum J, et al. Robust s41467-022-28544-w SARS-CoV-2-Specific T Cell Immunity is Maintained at 6 Months Following 101. Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser Primary Infection. Nat Immunol (2021) 22(5):620–6. doi: 10.1038/s41590- J, et al. Considerable Escape of SARS-CoV-2 Omicron to Antibody 021-00902-8 Neutralization. Nature (2021) 602: 671–67. doi: 10.1038/s41586-021- 119. Zhou R, To KKW, Wong YC, Liu L, Zhou B, Li X, et al. Acute SARS-CoV-2 04389-z Infection Impairs Dendritic Cell and T Cell Responses. Immunity (2020) 53 102. Wang Y, Zhang L, Li Q, Liang Z, Li T, Liu S, et al. The Significant Immune (4):864–77.e5. doi: 10.1016/j.immuni.2020.07.026 Escape of Pseudotyped SARS-CoV-2 Variant Omicron. Emerg Microbes 120. Liao L, Yang Gh. Clinical Significance of Cellular Immunity Function and Infect (2022) 11(1):1–5. doi: 10.1080/22221751.2021.2017757 Inflammatory Factors Assays in Alveolar Lavage Fluid for Severe COVID-19 103. Fenrich M, Mrdenovic S, Balog M, Tomic S, Zjalic M, Roncevic A, et al. Pneumonia. J Med Virol (2021) 93(5):2979–87. doi: 10.1002/jmv.26827 SARS-CoV-2 Dissemination Through Peripheral Nerves Explains 121. Gil-Manso S, Carbonell D, Ló pez-Ferná ndez L, Miguens I, Alonso R, Buño I, Multiple Organ Injury. Front Cell Neurosci (2020) 14. doi: 10.3389/ et al. Induction of High Levels of Specific Humoral and Cellular Responses to fncel.2020.00229 SARS-CoV-2 After the Administration of Covid-19 mRNA Vaccines 104. Tarke A, Sidney J, Methot N, Zhang Y, Dan JM, Goodwin B, et al. Negligible Requires Several Days. Front Immunol (2021) 12. doi: 10.3389/ Impact of SARS-CoV-2 Variants on CD4 + and CD8 + T Cell Reactivity in fimmu.2021.726960 C O VI D- 19 Ex p os ed D on o r s a n d Va c ci n e es . b i o Rx i v ( 20 2 1) 122. Domingo P, Mur I, Pomar V, Corominas H, Casademont J, de Benito N. The 1:2021.02.27.433180. doi: 10.1101/2021.02.27.433180 Four Horsemen of a Viral Apocalypse: The Pathogenesis of SARS-CoV-2 105. Tarke A, Sidney J, Kidd CK, Dan JM, Ramirez SI, Yu ED, et al. Infection (COVID-19). EBioMedicine (2020) 58:102887. doi: 10.1016/ C o mp r e he n s i v e An a l y s i s o f T C e l l I mm u n o d o mi n a n c e an d j.ebiom.2020.102887 Immunoprevalence of SARS-CoV-2 Epitopes in COVID-19 Cases. Cell 123. Baumgarth N, Nikolich-Ž ugich J, Lee FE-H, Bhattacharya D. Antibody Rep Med (2021) 2(2):100204. doi: 10.1016/j.xcrm.2021.100204 Responses to SARS-CoV-2: Let’s Stick to Known Knowns. J Immunol 106. Ferretti AP, Kula T, Wang Y, Nguyen DMV, Weinheimer A, Dunlap GS, (2020) 205(9):2342–50. doi: 10.4049/jimmunol.2000839 et al. Unbiased Screens Show CD8+ T Cells of COVID-19 Patients Recognize 124. Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Shared Epitopes in SARS-CoV-2 That Largely Reside Outside the Spike Weiskopf D, et al. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in P r ote i n . I m mu ni ty ( 20 2 0) 53 ( 5 ) : 1 09 5 – 10 7 . e 3. do i : 1 0 . 1 0 16 / Acute COVID-19 and Associations With Age and Disease Severity. Cell j.immuni.2020.10.006 (2020) 183(4):996–1012.e19. doi: 10.1016/j.cell.2020.09.038 Frontiers in Immunology | www.frontiersin.org 16 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 125. Tan AT, Linster M, Tan CW, Le Bert N, Chia WN, Kunasegaran K, et al. 144. Peng Y, Mentzer AJ, Liu G, Yao X, Yin Z, Dong D, et al. Broad and Strong Early Induction of Functional SARS-CoV-2-Specific T Cells Associates With Memory CD4+ and CD8+ T Cells Induced by SARS-CoV-2 in UK Rapid Viral Clearance and Mild Disease in COVID-19 Patients. Cell Rep Convalescent Individuals Following COVID-19. Nat Immunol (2020) 21 (2021) 34(6):108728. doi: 10.1016/j.celrep.2021.108728 (11):1336–45. doi: 10.1038/s41590-020-0782-6 126. Sekine T, Perez-Potti A, Rivera-Ballesteros O, Strålin K, Gorin J-B, Olsson A, 145. Kuri-Cervantes L, Pampena MB, Meng W, Rosenfeld AM, Ittner CAG, et al. Cell Immunity in Convalescent Individuals with Asymptomatic or Mild Weisman AR, et al. Comprehensive Mapping of Immune Perturbations COVID-19. Cell (2020) 183(1):158–68.e14. doi: 10.1016/j.cell.2020.08.017 Associated With Severe COVID-19. Sci Immunol (2020) 5(49):eabd7114. 127. Piccoli L, Park YJ, Tortorici MA, Czudnochowski N, Walls AC, Beltramello doi: 10.1126/sciimmunol.abd7114 M, et al. Mapping Neutralizing and Immunodominant Sites on the SARS- 146. Wen W, Su W, Tang H, Le W, Zhang X, Zheng Y, et al. Immune Cell CoV-2 Spike Receptor-Binding Domain by Structure-Guided High- Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Resolution Serology. Cell (2020) 183(4):1024–42.e21. doi: 10.1016/ Sequencing. Cell Discov (2020) 6(1):31. doi: 10.1038/s41421-020-00187-5 j.cell.2020.09.037 147. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. Single-Cell Landscape of 128. Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, et al. Bronchoalveolar Immune Cells in Patients With COVID-19. Nat Med (2020) Convergent Antibody Responses to SARS-CoV-2 in Convalescent 26(6):842–4. doi: 10.1038/s41591-020-0901-9 Individuals. Nature (2020) 584(7821):437–42. doi: 10.1038/s41586-020- 148. Ripperger TJ, Bhattacharya D. Transcriptional and Metabolic Control of 2456-9 Memory B Cells and Plasma Cells. Annu Rev Immunol (2021) 39:345–68. 129. Liu A, Li Y, Peng J, Huang Y, Xu D. Antibody Responses Against SARS- doi: 10.1146/annurev-immunol-093019-125603 CoV-2 in COVID-19 Patients. J Med Virol (2021) 93(1):144–8. doi: 10.1002/ 149. Victora GD, Nussenzweig MC. Germinal Centers. Annu Rev Immunol jmv.26241 (2012) 30:429–57. doi: 10.1146/annurev-immunol-020711-075032 130. Soresina A, Moratto D, Chiarini M, Paolillo C, Baresi G, Focà E, et al. Two X- 150. Crotty S. Follicular Helper CD4 T Cells (T Fh). Annu Rev Immunol (2011) Linked Agammaglobulinemia Patients Develop Pneumonia as COVID-19 29:621–63. doi: 10.1146/annurev-immunol-031210-101400 Manifestation But Recover. Pediatr Allergy Immunol (2020) 31(5):565–9. 151. Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T Follicular Helper doi: 10.1111/pai.13263 Cells in Humans and Mice. Nat Immunol (2015) 16(2):142–52. doi: 10.1038/ 131. Quinti I, Lougaris V, Milito C, Cinetto F, Pecoraro A, Mezzaroma I, et al. A ni.3054 Possible Role for B Cells in COVID-19? Lesson From Patients With 152. Turner JS, O’Halloran JA, Kalaidina E, Kim W, Schmitz AJ, Zhou JQ, et al. Agammaglobulinemia. J Allergy Clin Immunol (2020) 146(1):211–13.e4. SARS-CoV-2 mRNA Vaccines Induce Persistent Human Germinal Centre doi: 10.1016/j.jaci.2020.04.013 Responses. Nature (2021) 596(7870):109–13. doi: 10.1038/s41586-021- 132. Montero-Escribano P, Matı́as-Guiu J, Gó mez-Iglesias P, Porta-Etessam J, 03738-2 Pytel V, Matias-Guiu JA. Anti-CD20 and COVID-19 in Multiple Sclerosis 153. Turner JS, Zhou JQ, Han J, Schmitz AJ, Rizk AA, Alsoussi WB, et al. Human and Related Disorders: A Case Series of 60 Patients From Madrid, Spain. Germinal Centres Engage Memory and Naive B Cells After Influenza Mult Scler Relat Disord (2020) 42:102185. doi: 10.1016/j.msard.2020.102185 Vaccination. Nature (2020) 586(7827):127–32. doi: 10.1038/s41586-020- 133. Novi G, Mikulska M, Briano F, Toscanini F, Tazza F, Uccelli A, et al. 2711-0 COVID-19 in a MS Patient Treated With Ocrelizumab: Does 154. Kim W, Zhou JQ, Sturtz AJ, Horvath SC, Schmitz AJ, Lei T, et al. Germinal Immunosuppression Have a Protective Role? Mult Scler Relat Disord Centre-Driven Maturation of B Cell Response to SARS-CoV-2 Vaccination. (2020) 42:102120. doi: 10.1016/j.msard.2020.102120 bioRxiv (2021) 2:2021.10.31.466651. doi: 10.1101/2021.10.31.466651 134. Safavi F, Nourbakhsh B, Azimi AR. B-Cell Depleting Therapies May Affect 155. Mudd PA, Minervina AA, Pogorelyy MV, Turner JS, Kim W, Kalaidina E, Susceptibility to Acute Respiratory Illness Among Patients With Multiple et al. SARS-CoV-2 mRNA Vaccination Elicits a Robust and Persistent T Sclerosis During the Early COVID-19 Epidemic in Iran. Mult Scler Relat Follicular Helper Cell Response in Humans. Cell (2022) 185(4):603–13.e15. Disord (2020) 43:102195. doi: 10.1016/j.msard.2020.102195 doi: 10.1016/j.cell.2021 135. Creed MA, Ballesteros E, Greenfield LJ Jr, Imitola J. Mild COVID-19 156. Touizer E, Alrubayyi A, Rees-Spear C, Fisher-Pearson N, Griffith SA, Muir L, Infection Despite Chronic B Cell Depletion in a Patient With Aquaporin- et al. Failure to Seroconvert After Two Doses of BNT162b2 SARS-CoV-2 4-Positive Neuromyelitis Optica Spectrum Disorder. Mult Scler Relat Disord Vaccine in a Patient With Uncontrolled HIV. Lancet HIV (2021) 8(6):e317– (2020) 44:102199. doi: 10.1016/j.msard.2020.102199 8. doi: 10.1016/S2352-3018(21)00099-0 136. Avouac J, Airó P, Carlier N, Matucci-Cerinic M, Allanore Y. Severe COVID- 157. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three 19-Associated Pneumonia in 3 Patients With Systemic Sclerosis Treated Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. With Rituximab. Ann Rheum Dis (2020) annrheumdis-2020-217864. N Engl J Med (2021) 385(7):661–2. doi: 10.1056/NEJMc2108861 doi: 10.1136/annrheumdis-2020-217864 158. Kaneko N, Kuo HH, Boucau J, Farmer JR, Allard-Chamard H, Mahajan VS, 137. Bange EM, Han NA, Wileyto P, Kim JY, Gouma S, Robinson J, et al. CD8+ T et al. Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Cells Contribute to Survival in Patients With COVID-19 and Hematologic Centers in COVID-19. Cell (2020) 183(1):143–57.e13. doi: 10.1016/ Cancer. Nat Med (2021) 27(7):1280–9. doi: 10.1038/s41591-021-01386-7 j.cell.2020.08.025 138. Annunziato F, Romagnani C, Romagnani S. The 3 Major Types of Innate 159. Magleby R, Westblade LF, Trzebucki A, Simon MS, Rajan M, Park J, et al. and Adaptive Cell-Mediated Effector Immunity. J Allergy Clin Immunol Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load on (2015) 135(3):626–35. doi: 10.1016/j.jaci.2014.11.001 Risk of Intubation and Mortality Among Hospitalized Patients With 139. Iwasaki A, Medzhitov R. Control of Adaptive Immunity by the Innate Coronavirus Disease 2019. Clin Infect Dis (2021) 73(11):e4197–205. Immune System. Nat Immunol (2015) 16(4):343–53. doi: 10.1038/ni.3123 doi: 10.1093/cid/ciaa851 140. O’Shea J, Paul WE. Mechanisms Underlying Lineage Commitment and 160. Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional Exhaustion Plasticity of Helper CD4 + T Cells. Science (2010) 327(5969):1098–102. of Antiviral Lymphocytes in COVID-19 Patients. Cell Mol Immunol (2020) doi: 10.1126/science.1178334 17(5):533–5. doi: 10.1038/s41423-020-0402-2 141. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and 161. McMahan K, Yu J, Mercado NB, Loos C, Tostanoski LH, Chandrashekar A, Immunological Features of Severe and Moderate Coronavirus Disease 2019. et al. Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques. J Clin Invest (2020) 130(5):2620–9. doi: 10.1172/JCI137244 Nature (2021) 590(7847):630–4. doi: 10.1038/s41586-020-03041-6 142. Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, et al. 162. Wyllie DH, Mulchandani R, Jones HE, Taylor-Phillips S, Brooks T, Charlett Longitudinal Analyses Reveal Immunological Misfiring in Severe COVID- A, et al. Responsive T Cell Numbers Are Associated With Protection From 19. Nature (2020) 584(7821):463–9. doi: 10.1038/s41586-020-2588-y COVID-19: A Prospective Cohort Study in Keyworkers. medRxiv (2020) 143. GeurtsvanKessel CH, Geers D, Schmitz KS, Mykytyn AZ, Lamers MM, 04:2020.11.02.20222778. doi: 10.1101/2020.11.02.20222778. Bogers S, et al. Divergent SARS CoV-2 Omicron-Specific T- and B-Cell 163. Ni L, Cheng ML, Feng Y, Zhao H, Liu J, Ye F, et al. Impaired Cellular Responses in COVID-19 Vaccine Recipients. Sci Immunol (2022) 7(69): Immunity to SARS-CoV-2 in Severe COVID-19 Patients. Front Immunol eabo2202. doi: 10.1126/sciimmunol.abo2202 (2021) 12. doi: 10.3389/fimmu.2021.603563 Frontiers in Immunology | www.frontiersin.org 17 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 164. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological Findings 184. Melgaço JG, Brito E Cunha D, Azamor T, Da Silva AMV, Tubarão LN, of COVID-19 Associated With Acute Respiratory Distress Syndrome. Lancet Gonçalves RB, et al. Cellular and Molecular Immunology Approaches for the Respir Med (2020) 8(4):420–2. doi: 10.1016/S2213-2600(20)30076-X Development of Immunotherapies Against the New Coronavirus (SARS- 165. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and CoV-2): Challenges to Near-Future Breakthroughs. J Immunol Res (2020) Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 2020:8827670. doi: 10.1155/2020/8827670 (COVID-19). Front Immunol (2020) 11. doi: 10.3389/fimmu.2020.00827 185. Martonik D, Parfieniuk-Kowerda A, Rogalska M, Flisiak R. The Role of 166. Billerbeck E, Kang YH, Walker L, Lockstone H, Grafmueller S, Fleming V, Th17 Response in COVID-19. Cells (2021) 10(6):1550. doi: 10.3390/ et al. Analysis of CD161 Expression on Human CD8+ T Cells Defines a cells10061550 Distinct Functional Subset With Tissue-Homing Properties. Proc Natl Acad 186. Schulte-Schrepping J, Reusch N, Paclik D, Baßler K, Schlickeiser S, Zhang B, Sci USA (2010) 107(7):3006–11. doi: 10.1073/pnas.0914839107 et al. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell 167. Van Wilgenburg B, Scherwitzl I, Hutchinson EC, Leng T, Kurioka A, Kulicke Compartment. Cell (2020) 182(6):1419–40.e23. doi: 10.1016/ C, et al. MAIT Cells are Activated During Human Viral Infections. Nat j.cell.2020.08.001 Commun (2016) 7:11653. doi: 10.1038/ncomms11653 187. Deng Z, Zhang M, Zhu T, Zhili N, Liu Z, Xiang R, et al. Dynamic Changes in 168. Jouan Y, Guillon A, Gonzalez L, Perez Y, Boisseau C, Ehrmann S, et al. Peripheral Blood Lymphocyte Subsets in Adult Patients With COVID-19. Phenotypical and Functional Alteration of Unconventional T Cells in Severe Int J Infect Dis (2020) 98:353–8. doi: 10.1016/j.ijid.2020.07.003 COVID-19 Patients. J Exp Med (2020) 217(12):e20200872. doi: 10.1084/ 188. Wherry EJ. T Cell Exhaustion. Nat Immunol (2011) 12(6):492–9. jem.20200872 doi: 10.1038/ni.2035 169. Blanchard-Rohner G, Pulickal AS, Jol-van Der Zijde CM, Snape MD, Pollard 189. Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone AJ. Appearance of Peripheral Blood Plasma Cells and Memory B Cells in a MBA. Interleukin-10 Determines Viral Clearance or Persistence In Vivo. Nat Primary and Secondary Immune Response in Humans. Blood (2009) 114 Med (2006) 12(11):1301–9. doi: 10.1038/nm1492 (24):4998–5002. doi: 10.1182/blood-2009-03-211052 190. Zheng HY, Zhang M, Yang CX, Zhang N, Wang XC, Yang XP, et al. Elevated 170. Lee FE-H, Halliley JL, Walsh EE, Moscatiello AP, Kmush BL, Falsey AR, et al. Exhaustion Levels and Reduced Functional Diversity of T Cells in Peripheral Circulating Human Antibody-Secreting Cells During Vaccinations and Blood may Predict Severe Progression in COVID-19 Patients. Cell Mol Respiratory Viral Infections Are Characterized by High Specificity and Immunol (2020) 17(5):541–3. doi: 10.1038/s41423-020-0401-3 Lack of Bystander Effect. J Immunol (2011) 186(9):5514–21. doi: 10.4049/ 191. Kreutmair S, Unger S, Nú ñez NG, Ingelfinger F, Alberti C, De Feo D, et al. jimmunol.1002932 Distinct Immunological Signatures Discriminate Severe COVID-19 From 171. Wrammert J, Onlamoon N, Akondy RS, Perng GC, Polsrila K, Chandele A, non-SARS-CoV-2-Driven Critical Pneumonia. Immunity (2021) 54 et al. Rapid and Massive Virus-Specific Plasmablast Responses During Acute (7):1578–93.e5. doi: 10.1016/j.immuni.2021.05.002 Dengue Virus Infection in Humans. J Virol (2012) 86(6):2911–8. 192. Rha MS, Jeong HW, Ko JH, Choi SJ, Seo IH, Lee JS, et al. PD-1-Expressing doi: 10.1128/JVI.06075-11 SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, But Functional in 172. Moore JB, June CH. Cytokine Release Syndrome in Severe COVID-19. Sci Patients With COVID-19. Immunity (2021) 54(1):44–52.e3. doi: 10.1016/ (80- ) (2020) 368(6490):473–4. doi: 10.1126/science.abb8925 j.immuni.2020.12.002 173. Tay MZ, Poh CM, Ré nia L, MacAry PA, Ng LFP. The Trinity of COVID-19: 193. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry Immunity, Inflammation and Intervention. Nat Rev Immunol (2020) 20 EJ. Network Analysis Reveals Centrally Connected Genes and Pathways (6):363–74. doi: 10.1038/s41577-020-0311-8 Involved in CD8+ T Cell Exhaustion Versus Memory. Immunity (2012) 37 174. Guo XzJ, Thomas PG. New Fronts Emerge in the Influenza Cytokine Storm. (6):1130–44. doi: 10.1016/j.immuni.2012.08.021 Semin Immunopathol (2017) 39(5):541–50. doi: 10.1007/s00281-017-0636-y 194. Fuertes Marraco SA, Neubert NJ, Verdeil G, Speiser DE. Inhibitory 175. Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al. Relationships Among Receptors Beyond T Cell Exhaustion. Front Immunol (2015) 6(JUN). Lymphocyte Subsets, Cytokines, and the Pulmonary Inflammation Index in doi: 10.3389/fimmu.2015.00310 Coronavirus (COVID-19) Infected Patients. Br J Haematol (2020) 189 195. Singer M, Wang C, Cong L, Marjanovic ND, Kowalczyk MS, Zhang H, et al. (3):428–37. doi: 10.1111/bjh.16659 A Distinct Gene Module for Dysfunction Uncoupled From Activation in 176. Lee JS, Park S, Jeong HW, Ahn JY, Choi SJ, Lee H, et al. Immunophenotyping Tumor-Infiltrating T Cells. Cell (2016) 166(6):1500–11.e9. doi: 10.1016/ of Covid-19 and Influenza Highlights the Role of Type I Interferons in j.cell.2016.08.052 Development of Severe Covid-19. Sci Immunol (2020) 5(49):eabd1554. 196. Tirosh I, Izar B, Prakadan SM, Wadsworth MH, Treacy D, Trombetta JJ, doi: 10.1126/sciimmunol.abd1554 et al. Dissecting the Multicellular Ecosystem of Metastatic Melanoma by 177. Zhang Q, Liu Z, Moncada-Velez M, Chen J, Ogishi M, Bigio B, et al. Inborn Single-Cell RNA-Seq. Sci (2016) 352(6282):189–96. doi: 10.1126/ Errors of Type I IFN Immunity in Patients With Life-Threatening COVID- science.aad0501 19. Science (2020) 370(6515):eabd4570. doi: 10.1126/science.abd4570 197. Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, 178. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Chronic Virus Infection Enforces Demethylation of the Locus That et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of Encodes PD-1 in Antigen-Specific CD8+ T Cells. Immunity (2011) 35 COVID-19. Cell (2020) 181(5):1036–45.e9. doi: 10.1016/j.cell.2020.04.026 (3):400–12. doi: 10.1016/j.immuni.2011.06.015 179. Ferrucci L, Fabbri E. Inflammageing: Chronic Inflammation in Ageing, 198. Saris A, Reijnders TDY, Nossent EJ, Schuurman AR, Verhoeff J, Van Asten S, Cardiovascular Disease, and Frailty. Nat Rev Cardiol (2018) 15(9):505–22. et al. Distinct Cellular Immune Profiles in the Airways and Blood of doi: 10.1038/s41569-018-0064-2 Critically Ill Patients With COVID-19. Thorax (2021) 76(10):1010–9. 180. Shaw AC, Goldstein DR, Montgomery RR. Age-Dependent Dysregulation of doi: 10.1136/thoraxjnl-2020-216256 Innate Immunity. Nat Rev Immunol (2013) 13(12):875–87. doi: 10.1038/ 199. Vitte J, Diallo AB, Boumaza A, Lopez A, Michel M, Allardet-Servent J, et al. nri3547 A Granulocytic Signature Identifies COVID-19 and its Severity. J Infect Dis 181. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of (2020) 222(12):1985–96. doi: 10.1093/infdis/jiaa591 Immune Response in Patients With Coronavirus 2019 (COVID-19) in 200. Chen J, Vitetta L. Increased PD-L1 Expression may be Associated With the Wuhan, China. Clin Infect Dis (2020) 71(15):762–8. doi: 10.1093/cid/ciaa248 Cytokine Storm and CD8+T-Cell Exhaustion in Severe COVID-19. J Infect 182. Thieme CJ, Anft M, Paniskaki K, Blazquez-Navarro A, Doevelaar A, Seibert Dis (2021) 223(9):1659–60. doi: 10.1093/infdis/jiab061 FS, et al. Robust T Cell Response Toward Spike, Membrane, and 201. Sabbatino F, Conti V, Franci G, Sellitto C, Manzo V, Pagliano P, et al. PD-L1 Nucleocapsid SARS-CoV-2 Proteins Is Not Associated With Recovery in Dysregulation in COVID-19 Patients. Front Immunol (2021) 12. Critical COVID-19 Patients. Cell Rep Med (2020) 1(6):100092. doi: 10.1016/ doi: 10.3389/fimmu.2021.695242 j.xcrm.2020.100092 202. Eljaafari A, Pestel J, Le Magueresse-Battistoni B, Chanon S, Watson J, Robert 183. Vaz de Paula CB, de Azevedo MLV, Nagashima S, Martins APC, Malaquias M, et al. Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 MAS, Miggiolaro A, et al. IL-4/IL-13 Remodeling Pathway of COVID-19 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting Lung Injury. Sci Rep (2020) 10(1):18689. doi: 10.1038/s41598-020-75659-5 in T Cell Dysfunction. Cells (2021) 10(10):2645. doi: 10.3390/cells10102645 Frontiers in Immunology | www.frontiersin.org 18 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 203. Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal Convalescent Patients. Int J Infect Dis (2022) 115:208–14. doi: 10.1016/ R, et al. Tissue-Specific Immunopathology in Fatal COVID-19. Am J Respir j.ijid.2021.12.309 Crit Care Med (2021) 203(2):192–201. doi: 10.1164/rccm.202008-3265OC 222. Bonifacius A, Tischer-Zimmermann S, Dragon AC, Gussarow D, Vogel A, 204. Liu J, Yang X, Wang H, Li Z, Deng H, Liu J, et al. Analysis of the Long-Term Krettek U, et al. COVID-19 Immune Signatures Reveal Stable Antiviral T Impact on Cellular Immunity in COVID-19-Recovered Individuals Reveals a Cell Function Despite Declining Humoral Responses. Immunity (2021) 54 Profound Nkt Cell Impairment. MBio (2021) 12(2):e00085–21. doi: 10.1128/ (2):340–54.e6. doi: 10.1016/j.immuni.2021.01.008 mBio.00085-21 223. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-Month Consequences 205. Aid M, Busman-Sahay K, Vidal SJ, Maliga Z, Bondoc S, Starke C, et al. of COVID-19 in Patients Discharged From Hospital: A Cohort Study. Lancet Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus (2021) 397(10270):220–32. doi: 10.1016/S0140-6736(20)32656-8 Macaques. Cell (2020) 183(5):1354–66.e13. doi: 10.1016/j.cell.2020.10.005 224. Wheatley AK, Juno JA, Wang JJ, Selva KJ, Reynaldi A, Tan HX, et al. 206. Li S, Jiang L, Li X, Lin F, Wang Y, Li B, et al. Clinical and Pathological Evolution of Immune Responses to SARS-CoV-2 in Mild-Moderate COVID- Investigation of Patients With Severe COVID-19. JCI Insight (2020) 5(12): 19. Nat Commun (2021) 12(1):1162. doi: 10.1038/s41467-021-21444-5 e138070. doi: 10.1172/jci.insight.138070 225. Sherina N, Piralla A, Du L, Wan H, Kumagai-Braesch M, André ll J, et al. 207. Radermecker C, Detrembleur N, Guiot J, Cavalier E, Henket M, d’Emal C, Persistence of SARS-CoV-2-Specific B and T Cell Responses in Convalescent et al. Neutrophil Extracellular Traps Infiltrate the Lung Airway, Interstitial, COVID-19 Patients 6–8 Months After the Infection. Med (2021) 2(3):281– and Vascular Compartments in Severe COVID-19. J Exp Med (2020) 217 95.e4. doi: 10.1016/j.medj.2021.02.001 (12):e20201012. doi: 10.1084/jem.20201012 226. Rodda LB, Netland J, Shehata L, Pruner KB, Morawski PA, Thouvenel CD, 208. Schurink B, Roos E, Radonic T, Barbe E, Bouman CSC, de Boer HH, et al. et al. Functional SARS-CoV-2-Specific Immune Memory Persists After Viral Presence and Immunopathology in Patients With Lethal COVID-19: A Mild COVID-19. Cell (2021) 184(1):169–83.e17. doi: 10.1016/j.cell. Prospective Autopsy Cohort Study. Lancet Microbe (2020) 1(7):e290–9. 2020.11.029 doi: 10.1016/S2666-5247(20)30144-0 227. Jung JH, Rha MS, Sa M, Choi HK, Jeon JH, Seok H, et al. SARS-CoV-2- 209. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Specific T Cell Memory Is Sustained in COVID-19 Convalescent Patients for Wang B, et al. An Inflammatory Cytokine Signature Predicts COVID-19 10 Months With Successful Development of Stem Cell-Like Memory T Cells. Severity and Survival. Nat Med (2020) 26(10):1636–43. doi: 10.1038/s41591- Nat Commun (2021) 12(1):4043. doi: 10.1038/s41467-021-24377-1 020-1051-9 228. Grau-Expó sito J, Sá nchez-Gaona N, Massana N, Suppi M, Astorga-Gamaza 210. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex A, Perea D, et al. Peripheral and Lung Resident Memory T Cell Responses Differences in Immune Responses That Underlie COVID-19 Disease Against SARS-CoV-2. Nat Commun (2021) 12(1):3010. doi: 10.1038/s41467- Outcomes. Nature (2020) 588(7837):315–20. doi: 10.1038/s41586-020-2700-3 021-23333-3 211. Li C, Lee A, Grigoryan L, Arunachalam PS, Scott MKD, Trisal M, et al. 229. Szabo PA, Dogra P, Gray JI, Wells SB, Connors TJ, Weisberg SP, et al. Mechanisms of Innate and Adaptive Immunity to the Pfizer-BioNTech Longitudinal Profiling of Respiratory and Systemic Immune Responses BNT162b2 Vaccine. Nat Immunol (2022) 23:543–555. doi: 10.1038/ Reveals Myeloid Cell-Driven Lung Inflammation in Severe COVID-19. s41590-022-01163-9 Immunity (2021) 54(4):797–814.e6. doi: 10.1016/j.immuni.2021.03.005 212. Loske J, Röhmel J, Lukassen S, Stricker S, Magalhães VG, Liebig J, et al. Pre- 230. Mazzoni A, Vanni A, Spinicci M, Lamacchia G, Kiros ST, Rocca A, et al. Activated Antiviral Innate Immunity in the Upper Airways Controls Early SARS-CoV-2 Infection and Vaccination Trigger Long-Lived B and CD4+ T SARS-CoV-2 Infection in Children. Nat Biotechnol (2021) 40:319–24. Lymphocytes: Implications for Booster Strategies. J Clin Invest (2022) 132(6): doi: 10.1101/2021.06.24.21259087 e157990. doi: 10.1172/JCI157990 213. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, 231. Vinuesa CG, Linterman MA, Yu D, Maclennan ICM. Follicular Helper T et al. Multisystem Inflammatory Syndrome in Children in New York State. N Cells. Annu Rev Immunol (2016) 34:335–68. doi: 10.1146/annurev- Engl J Med (2020) 383(4):347–58. doi: 10.1056/NEJMoa2021756 immunol-041015-055605 214. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, 232. Juno JA, Tan HX, Lee WS, Reynaldi A, Kelly HG, Wragg K, et al. Humoral et al. Multisystem Inflammatory Syndrome in U.S. Children and and Circulating Follicular Helper T Cell Responses in Recovered Patients Adolescents. N Engl J Med (2020) 383(4):334–46. doi: 10.1056/ With COVID-19. Nat Med (2020) 26(9):1428–34. doi: 10.1038/s41591-020- NEJMoa2021680 0995-0 215. Weisberg SP, Connors TJ, Zhu Y, Baldwin MR, Lin WH, Wontakal S, et al. 233. Boppana S, Qin K, Files JK, Russell RM, Stoltz R, Bibollet-Ruche F, et al. Distinct Antibody Responses to SARS-CoV-2 in Children and Adults Across SARS-CoV-2-Specific Circulating T Follicular Helper Cells Correlate With the COVID-19 Clinical Spectrum. Nat Immunol (2021) 22(1):25–31. Neutralizing Antibodies and Increase During Early Convalescence. PLoS doi: 10.1038/s41590-020-00826-9 Pathog (2021) 17(7):e1009761. doi: 10.1371/journal.ppat.1009761 216. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. 234. Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Clinical Characteristics of 58 Children With a Pediatric Inflammatory Tuong ZK, et al. Single-Cell Multi-Omics Analysis of the Immune Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA Response in COVID-19. Nat Med (2021) 27(5):904–16. doi: 10.1038/ - J Am Med Assoc (2020) 324(3):259–69. doi: 10.1001/jama.2020.10369 s41591-021-01329-2 217. Zhang J, Lin H, Ye B, Zhao M, Zhan J, Dong S, et al. One-Year Sustained 235. Northfield JW, Loo CP, Barbour JD, Spotts G, Hecht FM, Klenerman P, et al. Cellular and Humoral Immunities of COVID-19 Convalescents. Clin Infect Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8 + T EMRA Dis (2021) ciab884. doi: 10.1093/cid/ciab884 Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict 218. Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. Immunological the Subsequent Viral Load Set Point. J Virol (2007) 81(11):5759–65. Memory to SARS-CoV-2 Assessed for Up to 8 Months After Infection. doi: 10.1128/JVI.00045-07 Science (2021) 371(6529):eabf4063. doi: 10.1126/science.abf4063 236. Lilleri D, Fornara C, Revello MG, Gerna G. Human Cytomegalovirus- 219. Bilich T, Nelde A, Heitmann JS, Maringer Y, Roerden M, Bauer J, et al. T Cell Specific Memory CD8+ and CD4+ T Cell Differentiation After Primary and Antibody Kinetics Delineate SARS-CoV-2 Peptides Mediating Long- Infection. J Infect Dis (2008) 198(4):536–43. doi: 10.1086/590118 Term Immune Responses in COVID-19 Convalescent Individuals. Sci Transl 237. Akondy RS, Monson ND, Miller JD, Edupuganti S, Teuwen D, Wu H, et al. Med (2021) 13(590):eabf7517. doi: 10.1126/scitranslmed.abf7517 The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human 220. He Z, Ren L, Yang J, Guo L, Feng L, Ma C, et al. Seroprevalence and Humoral Memory CD8 + T Cell Response. J Immunol (2009) 183(12):7919–30. Immune Durability of Anti-SARS-CoV-2 Antibodies in Wuhan, China: A doi: 10.4049/jimmunol.0803903 Longitudinal, Population-Level, Cross-Sectional Study. Lancet (2021) 397 238. Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, Soares MVD, (10279):1075–84. doi: 10.1016/S0140-6736(21)00238-5 et al. Epstein-Barr Virus-Specific CD8+ T Cells That Re-Express CD45RA 221. Gurevich M, Zilkha-Falb R, Sonis P, Magalashvili D, Menascu S, Flechter S, are Apoptosis-Resistant Memory Cells That Retain Replicative Potential. et al. SARS-CoV-2 Memory B and T Cell Profiles in Mild COVID-19 Blood (2002) 100(3):933–40. doi: 10.1182/blood-2002-01-0160 Frontiers in Immunology | www.frontiersin.org 19 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 239. Adamo S, Michler J, Zurbuchen Y, Cervia C, Taeschler P, Raeber ME, et al. 258. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, Signature of Long-Lived Memory CD8+ T Cells in Acute SARS-CoV-2 et al. An mRNA Vaccine Against SARS-CoV-2 — Preliminary Report. N Infection. Nature (2022) 602(7895):148–55. doi: 10.1038/s41586-021-04280-x Engl J Med (2020) 383(20):1920–31. doi: 10.1056/NEJMoa2022483 240. Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K. Type I 259. Saadat S, Rikhtegaran Tehrani Z, Logue J, Newman M, Frieman MB, Harris Interferons Act Directly on CD8 T Cells to Allow Clonal Expansion and AD, et al. Binding and Neutralization Antibody Titers After a Single Vaccine Memory Formation in Response to Viral Infection. J Exp Med (2005) 202 Dose in Health Care Workers Previously Infected With SARS-CoV-2. JAMA (5):637–50. doi: 10.1084/jem.20050821 - J Am Med Assoc (2021) 325(14):1467–9. doi: 10.1001/jama.2021.3341 241. Derhovanessian E, Maier AB, Hähnel KH, Beck R, de Craen AJM, Slagboom 260. McDade TW, Demonbreun AR, Sancilio A, Mustanski B, D’Aquila RT, EP, et al. Infection With Cytomegalovirus But Not Herpes Simplex Virus McNally EM. Durability of Antibody Response to Vaccination and Surrogate Induces the Accumulation of Latedifferentiated CD4 + and CD8 + T-Cells in Neutralization of Emerging Variants Based on SARS-CoV-2 Exposure Humans. J Gen Virol (2011) 92(12):2746–56. doi: 10.1099/vir.0.036004-0 History. Sci Rep (2021) 11(1):17325. doi: 10.1038/s41598-021-96879-3 242. Visvabharathy L, Hanson B, Orban Z, Lim PH, Palacio N, Jain R, et al. 261. Naaber P, Tserel L, Kangro K, Sepp E, Jürjenson V, Adamson A, et al. Neuro-COVID Long-Haulers Exhibit Broad Dysfunction in T Cell Memory Dynamics of Antibody Response to BNT162b2 Vaccine After Six Months: A Gener ation and R espo ns es to Vacc ination. m ed Rx i v (2 02 1 ) Longitudinal Prospective Study. Lancet Reg Health Eur (2021) 10:100208. 29:2021.08.08.21261763. doi: 10.1101/2021.08.08.21261763 doi: 10.1016/j.lanepe.2021.100208 243. Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T Memory Stem Cells in 262. Quast I, Tarlinton D. B Cell Memory: Understanding COVID-19. Immunity Health and Disease. Nat Med (2017) 23(1):18–27. doi: 10.1038/nm.4241 (2021) 54(2):205–10. doi: 10.1016/j.immuni.2021.01.014 244. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A Human 263. Khodadadi L, Cheng Q, Radbruch A, Hiepe F. The Maintenance of Memory Memory T Cell Subset With Stem Cell-Like Properties. Nat Med (2011) 17 Plasma Cells. Front Immunol (2019) 10. doi: 10.3389/fimmu.2019.00721 (10):1290–7. doi: 10.1038/nm.2446 264. Chivu-Economescu M, Bleotu C, Grancea C, Chiriac D, Botezatu A, Iancu 245. Cohen KW, Linderman SL, Moodie Z, Czartoski J, Lai L, Mantus G, et al. IV, et al. Kinetics and Persistence of Cellular and Humoral Immune Longitudinal Analysis Shows Durable and Broad Immune Memory After Responses to SARS-CoV-2 Vaccine in Healthcare Workers With or SARS-CoV-2 Infection With Persisting Antibody Responses and Memory B Without Prior COVID-19. J Cell Mol Med (2022) 26(4):1293–305. and T Cells. Cell Rep Med (2021) 2(7):100354. doi: 10.1101/ doi: 10.1111/jcmm.17186 2021.04.19.21255739 265. Schmidt T, Klemis V, Schub D, Schneitler S, Reichert MC, Wilkens H, et al. 246. Forthal D. Adaptive Immune Responses to SARS-CoV-2. Adv Drug Delivery Cellular Immunity Predominates Over Humoral Immunity After Rev (2021) 172:1–8. doi: 10.1016/j.addr.2021.02.009 Homologous and Heterologous mRNA and Vector-Based COVID-19 247. Galletti G, De Simone G, Mazza EMC, Puccio S, Mezzanotte C, Bi TM, et al. Vaccine Regimens in Solid Organ Transplant Recipients. Am J Transplant Two Subsets of Stem-Like CD8+ Memory T Cell Progenitors With Distinct (2021) 21(12):3990–4002. doi: 10.1111/ajt.16818 Fate Commitments in Humans. Nat Immunol (2020) 21(12):1552–62. 266. Zhu J. T Helper 2 (Th2) Cell Differentiation, Type 2 Innate Lymphoid Cell doi: 10.1038/s41590-020-0791-5 (ILC2) Development and Regulation of Interleukin-4 (IL-4) and IL-13 248. Cox RJ, Brokstad KA. Not Just Antibodies: B Cells and T Cells Mediate Production. Cytokine (2015) 75(1):14–24. doi: 10.1016/j.cyto.2015.05.010 Immunity to COVID-19. Nat Rev Immunol (2020) 20(10):581–2. 267. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, et al. A doi: 10.1038/s41577-020-00436-4 Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus 249. Mazzoni A, Di Lauria N, Maggi L, Salvati L, Vanni A, Capone M, et al. First- Vaccine Provides Incomplete Protection in Mice and Induces Increased Dose mRNA Vaccination is Sufficient to Reactivate Immunological Memory Eosinophilic Proinflammatory Pulmonary Response Upon Challenge. J Virol to SARS-CoV-2 in Subjects Who Have Recovered From COVID-19. J Clin (2011) 85(23):12201–15. doi: 10.1128/JVI.06048-11 Invest (2021) 131(12):e149150. doi: 10.1172/JCI149150 268. Agrawal AS, Tao X, Algaissi A, Garron T, Narayanan K, Peng BH, et al. 250. Painter MM, Mathew D, Goel RR, Apostolidis SA, Pattekar A, Kuthuru O, Immunization With Inactivated Middle East Respiratory Syndrome et al. Rapid Induction of Antigen-Specific CD4+ T Cells is Associated With Coronavirus Vaccine Leads to Lung Immunopathology on Challenge With Coordinated Humoral and Cellular Immunity to SARS-CoV-2 mRNA Live Virus. Hum Vaccines Immunother (2016) 12(9):2351–6. doi: 10.1080/ Vaccination. Immunity (2021) 54(9):2133–42.e3. doi: 10.1016/ 21645515.2016.1177688 j.immuni.2021.08.001 269. Yasui F, Kai C, Kitabatake M, Inoue S, Yoneda M, Yokochi S, et al. Prior 251. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Immunization With Severe Acute Respiratory Syndrome (SARS)-Associated Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia (2020) 383(27):2603–15. doi: 10.1056/NEJMoa2034577 in Mice Infected With SARS-CoV. J Immunol (2008) 181(9):6337–48. 252. Kalimuddin S, Tham CYL, Qui M, de Alwis R, Sim JXY, Lim JME, et al. Early doi: 10.4049/jimmunol.181.9.6337 T Cell and Binding Antibody Responses are Associated With COVID-19 270. Iwata-Yoshikawa N, Uda A, Suzuki T, Tsunetsugu-Yokota Y, Sato Y, RNA Vaccine Efficacy Onset. Med (2021) 2(6):682–88.e4. doi: 10.1016/ Morikawa S, et al. Effects of Toll-Like Receptor Stimulation on j.medj.2021.04.003 Eosinophilic Infiltration in Lungs of BALB/c Mice Immunized With UV- 253. Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, et al. Inactivated Severe Acute Respiratory Syndrome-Related Coronavirus COVID-19 Vaccine BNT162b1 Elicits Human Antibody and TH1 T Cell Vaccine. J Virol (2014) 88(15):8597–614. doi: 10.1128/JVI.00983-14 Responses. Nature (2020) 586(7830):594–9. doi: 10.1038/s41586-020-2814-7 271. Xu K, Dai L, Gao GF. Humoral and Cellular Immunity and the Safety of 254. Sahin U, Muik A, Vogler I, Derhovanessian E, Kranz LM, Vormehr M, et al. COVID-19 Vaccines: A Summary of Data Published by 21 May 2021. Int BNT162b2 Vaccine Induces Neutralizing Antibodies and Poly-Specific T Immunol (2021) 33(10):529–40. doi: 10.1093/intimm/dxab061 Cells in Humans. Nature (2021) 595(7868):572–7. doi: 10.1038/s41586-021- 272. Krawczyk CM, Shen H, Pearce EJ. Memory CD4 T Cells Enhance Primary 03653-6 CD8 T-Cell Responses. Infect Immun (2007) 75(7):3556–60. doi: 10.1128/ 255. Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, et al. IAI.00086-07 Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA Vaccine-Elicited Antibodies. 273. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4 +T Cells: Differentiation Nature (2021) 593(7857):136–41. doi: 10.1038/s41586-021-03412-7 and Functions. Clin Dev Immunol (2012) 2012:925135. doi: 10.1155/2012/ 256. Wang Z, Schmidt F, Weisblum Y, Muecksch F, Barnes CO, Finkin S, et al. 925135 mRNA Vaccine-Elicited Antibodies to SARS-CoV-2 and Circulating 274. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 Signals During Priming Variants. Nature (2021) 592(7855):616–22. doi: 10.1038/s41586-021-03324-6 are Required for Secondary Expansion of CD8+ Memory T Cells. Nature 257. Goel RR, Apostolidis SA, Painter MM, Mathew D, Pattekar A, Kuthuru O, (2006) 441(7095):890–3. doi: 10.1038/nature04790 et al. Distinct Antibody and Memory B Cell Responses in SARSCoV-2 Naïve 275. Oberhardt V, Luxenburger H, Kemming J, Schulien I, Ciminski K, Giese S, and Recovered Individuals Following mRNA Vaccination. Sci Immunol et al. Rapid and Stable Mobilization of CD8+ T Cells by SARS-CoV-2 mRNA (2021) 6(58):1–19. doi: 10.1126/sciimmunol.abi6950 Vaccine. Nature (2021) 597(7875):268–73. doi: 10.1038/s41586-021-03841-4 Frontiers in Immunology | www.frontiersin.org 20 June 2022 | Volume 13 | Article 904686 Moga et al. Robustness Cellular SARS-CoV-2 Immunity 276. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy Induced by a SARS-CoV-2 Inactivated Vaccine. Front Immunol (2021) 12. and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med (2021) doi: 10.3389/fimmu.2021.747830 384(5):403–16. doi: 10.1056/NEJMoa2035389 286. Riou C, Keeton R, Moyo-Gwete T, Hermanus T, Kgagudi P, Baguma R, et al. 277. Lustig Y, Nemet I, Kliker L, Zuckerman N, Yishai R, Alroy-Preis S, et al. Escape From Recognition of SARS-CoV-2 Variant Spike Epitopes But Neutralizing Response Against Variants After SARS-CoV-2 Infection and Overall Preservation of T Cell Immunity. Sci Transl Med (2022) 14(631): One Dose of BNT162b2. N Engl J Med (2021) 384(25):2453–4. doi: 10.1056/ eabj6824. doi: 10.1126/scitranslmed.abj6824 NEJMc2104036 287. Zimmermann P, Curtis N. Factors That Influence the Immune Response to 278. Goel RR, Painter MM, Apostolidis SA, Mathew D, Meng W, Rosenfeld AM, Vaccination. Clin Microbiol Rev (2019) 32(2):e00084-18. doi: 10.1128/ et al. mRNA Vaccines Induce Durable Immune Memory to SARS-CoV-2 CMR.00084-18 and Variants of Concern. Sci (2021) 374(6572):abm0829. doi: 10.1126/ 288. Collier DA, Ferreira IATM, Kotagiri P, Datir RP, Lim EY, Touizer E, et al. science.abm0829 Age-Related Immune Response Heterogeneity to SARS-CoV-2 Vaccine 279. Collier A-RY, Brown CM, Mcmahan K, Yu J, Liu J, Jacob-Dolan C, et al. BNT162b2. Nature (2021) 596(7872):417–22. doi: 10.1038/s41586-021- Immune Responses in Fully Vaccinated Individuals Following Breakthrough 03739-1 Infection With the SARS-CoV-2 Delta Variant in Provincetown, 289. Witkowski W, Gerlo S, De Smet E, Wejda M, Acar D, Callens S, et al. Massachusetts. medRxiv (2021) 20:2021.10.18.21265113. doi: 10.1101/ Humoral and Cellular Responses to COVID-19 Vaccination Indicate the 2021.10.18.21265113 Need for Post-Vaccination Testing in Frail Population. Vaccines (2022) 10 280. Tarke A, Sidney J, Methot N, Yu ED, Zhang Y, Dan JM, et al. Impact of (2):260. doi: 10.3390/vaccines10020260 SARS-CoV-2 Variants on the Total CD4+ and CD8+ T Cell Reactivity in 290. Van Praet JT, Vandecasteele S, De Roo A, Vynck M, De Vriese AS, Reynders Infected or Vaccinated Individuals. Cell Rep Med (2021) 2(7):100355. M. Dynamics of the Cellular and Humoral Immune Response After doi: 10.1016/j.xcrm.2021.100355 BNT162b2 Messenger Ribonucleic Acid Coronavirus Disease 2019 281. Tarke A, Coelho CH, Zhang Z, Dan JM, Yu ED, Methot N, et al. SARS-CoV- (COVID-19) Vaccination in COVID-19-Naive Nursing Home Residents. 2 Vaccination Induces Immunological T Cell Memory Able to Cross- J Infect Dis (2021) 224(10):1690–3. doi: 10.1093/infdis/jiab458 Recognize Variants From Alpha to Omicron. Cell (2022) 185(5):847– 59.e11. doi: 10.1101/2021.12.28.474333 Conflict of Interest: The authors declare that the research was conducted in the 282. Gao Y, Cai C, Grifoni A, Müller TR, Niessl J, Olofsson A, et al. Ancestral absence of any commercial or financial relationships that could be construed as a SARS-CoV-2-Specific T Cells Cross-Recognize the Omicron Variant. Nat potential conflict of interest. Med (2022) 28:472–6. doi: 10.1038/s41591-022-01700-x 283. Geers D, Shamier MC, Bogers S, den Hartog G, Gommers L, Nieuwkoop Publisher’s Note: All claims expressed in this article are solely those of the authors NN, et al. SARS-CoV-2 Variants of Concern Partially Escape Humoral and do not necessarily represent those of their affiliated organizations, or those of But Not T-Cell Responses in COVID-19 Convalescent Donors and the publisher, the editors and the reviewers. Any product that may be evaluated in Vaccinees. Sci Immunol (2021) 6(59):eabj1750. doi: 10.1126/sciimmunol this article, or claim that may be made by its manufacturer, is not guaranteed or .abj1750 endorsed by the publisher. 284. Keeton R, Richardson SI, Moyo-Gwete T, Hermanus T, Tincho MB, Benede N, et al. Prior Infection With SARS-CoV-2 Boosts and Broadens Copyright © 2022 Moga, Lynton-Pons and Domingo. This is an open-access article Ad26.COV2.S Immunogenicity in a Variant-Dependent Manner. Cell distributed under the terms of the Creative Commons Attribution License (CC BY). Host Microbe (2021) 29(11):1611–19.e5. doi: 10.1016/j.chom.2021. The use, distribution or reproduction in other forums is permitted, provided the 10.003 original author(s) and the copyright owner(s) are credited and that the original 285. Melo-Gonzá lez F, Soto JA, Gonzá lez LA, Ferná ndez J, Duarte LF, Schultz publication in this journal is cited, in accordance with accepted academic practice. No BM, et al. Recognition of Variants of Concern by Antibodies and T Cells use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 21 June 2022 | Volume 13 | Article 904686