MINI REVIEW published: 28 July 2021 doi: 10.3389/fimmu.2021.712109 Swine Dendritic Cell Response to Porcine Reproductive and Respiratory Syndrome Virus: An Update Jesús Hernández 1*, Yanli Li 2 and Enric Mateu 2,3 1 Laboratorio de Inmunologı´a, Centro de Investigación en Alimentación y Desarrollo, Hermosillo, Mexico, 2 Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain, 3 IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Cerdanyola del Vallès, Spain Dendritic cells (DCs) are the most potent antigen-presenting cells, unique to initiate and coordinate the adaptive immune response. In pigs, conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs) have been described in blood and tissues. Different pathogens, such as viruses, could infect these cells, and in some cases, compromise their response. The understanding of the interaction between Edited by: DCs and viruses is critical to comprehend viral immunopathological responses. Porcine Falko Steinbach, reproductive and respiratory syndrome virus (PRRSV) is the most important respiratory University of Surrey, pathogen in the global pig population. Different reports support the notion that PRRSV United Kingdom modulates pig immune response in addition to their genetic and antigenic variability. The Reviewed by: Sanipa Suradhat, interaction of PRRSV with DCs is a mostly unexplored area with conflicting results and lots Chulalongkorn University, of uncertainties. Among the scarce certainties, cDCs and pDCs are refractory to PRRSV Thailand Andrea Ladinig, infection in contrast to moDCs. Additionally, response of DCs to PRRSV can be different University of Veterinary depending on the type of DCs and maybe is related to the virulence of the viral isolate. The Medicine Vienna, Austria precise impact of this virus-DC interaction upon the development of the specific immune *Correspondence: response is not fully elucidated. The present review briefly summarizes and discusses the Jesús Hernández jhdez@ciad.mx previous studies on the interaction of in vitro derived bone marrow (bm)- and moDCs, and in vivo isolated cDCs, pDCs, and moDCs with PRRSV1 and 2. Specialty section: This article was submitted to Keywords: PRRSV, dendritic cell, cDC1, cCD2, pDCs, bmDCs, moDCs Comparative Immunology, a section of the journal Frontiers in Immunology INTRODUCTION Received: 19 May 2021 Accepted: 07 July 2021 Porcine reproductive and respiratory syndrome (PRRS) is one of the most important diseases Published: 28 July 2021 affecting the swine industry worldwide. It causes reproductive failure in sows and respiratory Citation: distress, growth reduction, and high mortality in young pigs (1). Economically, it is important for Hernández J, Li Y and Mateu E (2021) the affected farms; for example, losses associated with the disease were estimated at 644 million USD Swine Dendritic Cell Response to Porcine Reproductive and Respiratory annually for US farms (2). The etiological agents of PRRS are two enveloped positive-sense RNA Syndrome Virus: An Update. viruses designated as porcine reproductive and respiratory syndrome virus (PRRSV) 1 and 2. Both Front. Immunol. 12:712109. PRRSV viruses belong to the family Arteriviridae, genus Betaarterivirus (3). PRRSV genome is about doi: 10.3389/fimmu.2021.712109 15 kb in length containing at least ten open reading frames (ORFs) flanked by two untranslated Frontiers in Immunology | www.frontiersin.org 1 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs regions at 5’ and 3’ ends. The ORFs1a and 1b encompass about cDC1 subtype as XCR1hiCADM1hiCD172alowIRF8hiIRF4lo, and the 80% of the viral genome and encode two polyproteins that are cDC2 subtype as XCR1-CD172ahiIRF8loIRF4hi (21). In swine, cleaved into 14 non-structural proteins (nsp1-nsp14). ORF2a, significant contributions have been made in the last years, ORF2b, ORFs 3 - 7, and ORF5a genes encode eight structural allowing identifying cDCs, and the cDC1 and cDC2 subtypes proteins: GP2, E, GP3, GP4, GP5, M, N, and ORF5a protein, from blood (22, 23), lymph nodes (24, 25), skin (26), and lung respectively (4). (27). In all these reports, cDC1 and cDC2 have been characterized, Non-structural proteins are essential for viral replication, are although in some cases the labeling strategy was different. These recognized by the immune system, and have been involved in differences will not be further discussed in this review. regulating of the immune response (5). Structural proteins have Monocytes may capture antigens, present them in the been implicated in the modulation of host innate immune histocompatibility complex and differentiate into the so-called response and the induction of antigen-specific B- and T-cell moDCs in peripheral non-lymphoid organs, particularly under responses [Reviewed by Loving et al. (6)]. After infection, pigs inflammatory conditions (28). In vivo generated moDCs may rapidly develop antibodies, but those early antibodies are devoid possess the cross-presentation ability and are able to transfer of neutralizing capacities. Antibodies with neutralizing activity antigens to DCs present in lymph nodes, thus being important in appear later, usually after the fourth week of infection (7). These developing an immune response to pathogens [see (28) for a antibodies are mainly directed against GP2, GP3, GP4, and GP5, review on the role of moDC]. It is worth mentioning that moDCs proteins interacting with CD163 (GP2-GP4) and porcine were increased in lungs of PRRSV-infected animals (29). moDCs sialoadhesin (Siglec-1, GP5) which are the main receptors and bmDCs have been extensively used in in vitro studies as well mediating PRRSV entry into the target cells (8). The induction to analyze the interaction between PRRSV and DCs. Most of of PRRSV-specific IFN-g-secreting cells (IFN-g-SC) also occurs those reports used a similar strategy consisting of culturing relatively late in the course of the infection (7, 9) which is monocytes or bone-marrow cells with GM-CSF with or considered an indicator of the development of cell-mediated without the addition of IL-4 to differentiate DCs. These immunity. It has been proved that both structural and non- protocols will neither be discussed, and only specific structural viral proteins induce IFN-g-SC (10–12). annotations will be done if necessary. The delayed development of neutralizing antibodies and late production of cell-mediated responses result in prolonged viremia and persistence of the virus in lymphoid tissues for several weeks. Different hypotheses have been proposed to MONOCYTE- AND BONE MARROW- explain this unusual immune response, many of them DERIVED DCs RESPONSE TO PRRSV suggesting that the interaction of the virus with dendritic cells For many years, the difficulty for having ex vivo cDC or for may be the main cause. This review discusses the response and deriving them from precursors render moDCs and bmDCs a modulatory effects of PRRVS on monocyte- (mo-), bone- useful method to evaluate the response of DCs to PRRSV. Both marrow- (bm) derived DCs, conventional DCs (cDCs), and moDCs and bmDCs are heterogeneous cell populations that plasmacytoid DCs (pDCs). include subsets susceptible to infection and replication, allowing to evaluate the effects of infection and co-infection with other pathogens. Most studies indicated that both PRRSV1 and 2 could DENDRITIC CELLS enter and replicate in moDCs (30–34) and bmDCs (35) with one study indicating lower susceptibility of moDCs than bmDCs DCs are professional antigen-presenting cells. They sense the (36). The viral yield after infection may differ in bmDCs and presence of invading antigens, then migrate to the lymph nodes, moDCs (37) and not all strains would have the same replication particularly the T cell-rich zones, to trigger naïve lymphocytes rates in moDCs as those obtained in monocyte-derived into distinct classes of effector cells, finally initiate the T cell- macrophages (38). These differences could be explained by the mediated immunity (13, 14). There are mainly two types of DCs: low proportion of CD163pos (and to a less extent by the low plasmacytoid DCs (pDCs) and myeloid conventional or classical expression of Siglec-1/CD169 in moDCs) or participation of DCs (cDCs). cDCs are further divided into two subtypes or other receptors (38). subsets: cDC1 and cDC2 (15). pDCs are responsible for One of the main focuses when studying the interaction of producing interferon-alpha (IFN-a) in response to viral PRRSV with moDCs and bmDCs is the cytokine patterns after infections, but are less efficient at T-cell priming than cDCs exposure to PRRSV. IL-10 is a potent anti-inflammatory (16). In contrast, cDCs are the most professional antigen- cytokine with a broad range of effects on the immune response presenting cells. The cDC1 subset is thought to drive naïve T against viral infections. It is produced by a variety of cells, cells into Th1 cells and cross-present antigens to CD8 T cells (17). including DCs. It has been reported that pathogens inducing The cDC2 subtype stimulates CD4 T cells to promote Th2 and IL-10 at early phases of the immune response could compromise Th17 cells (18, 19). the resolution of infection, and in some cases, lead to persistent The cDC1 and cDC2 subtypes have been characterized in several infection or promote maintenance of persistent infection (39). species, including swine (20). Using common markers shared by Production of IL-10 by PRRSV-infected DCs remains humans, macaques, and mice, Guilliams et al. (21) identified the controversial. Some authors reported significant production Frontiers in Immunology | www.frontiersin.org 2 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs after infection of moDCs (31, 32, 40) or bmDCs (35, 41, 42), However, in other models such as the co-infection with PCV2, while others reported either a non-significant induction of this the predominant regulatory cytokine was TGF-b although its cytokine (30, 43) or that IL-10 production was strain-dependent level could not be correlated with the number of Tregs (46). (44, 45). In other cases, IL-10 was produced only when moDCs The discussion above suggests that PRRSV2 can induce Tregs were co-infected with PRRSV and other agents such as PCV2 but through moDCs-mediated antigen presentation, but it remains not by PRRSV alone (46). These studies suggest that IL-10 unknown whether bona fide DCs could also induce Tregs since production may depend on several factors including, but they are not susceptible (discussed below). It is also unclear how maybe not limited to, the maturation stage of DCs and the Tregs contribute to the immunopathogenesis of PRRSV, or if they PRRSV strain used. Also, it could be enhanced by coinfection or only represent a homeostatic response to inflammatory events. superinfection with other pathogens. In vivo production of IL-10 In addition to the induction of Tregs, Nedumpun et al. has been more consistently reported, suggesting that in addition showed that PRRSV-infected moDCs induced the expression to DCs, other cells, such as macrophages, in the lung or lymphoid and production of IL-1Ra, which is a natural suppressor of the tissues, could be important sources of this cytokine during inflammatory response (59, 60). Chen et al. (61) demonstrated PRRSV infection (47). Liu et al. (36) proposed that IL-10 that the viral N protein and nsp10 enhanced the production of production was predominant in PRRSV-infected moDCs, CD83, an inhibitor of DC-mediated T-cell proliferation (62), via suppressing the production of Th1 cytokines, such as IL-12, activation of NF-KB and Sp1 signaling pathways (61). and finally regulating the polarization of Th1/Th2. The effects of co-infection or super-infection on the It has been reported that several pathogens can induce T functionality of DCs have been evaluated with different in vitro regulatory cells (Tregs) [reviewed by Maizels and Smith (48)]. models. Concomitant infections frequently occur in the field and Tregs are important sources of regulatory cytokines (IL-10 or PRRSV infection can have an impact on the response of DCs TGF-b) which can suppress or delay naïve T-cell priming and against other pathogens of pigs. For example, exposure to proliferation, (49) thus impairing the protective responses. Two PRRSV impaired the capacity of bmDCs in ingesting main types of Tregs, natural (n) and induced (i), have been Streptococcus suis (S. suis) although the killing of phagocytized recognized (50). nTregs arise in the thymus, while iTregs arise in bacteria was not affected. In the same study, PRRSV and S. suis the periphery following CD4+ T-cell activation in the presence of showed a synergistic interaction on the expression of chemokines TGF-b or upon stimulation with IL-2 or exposure to some and pro-inflammatory cytokines (37). In another study, pathogens (50). coinfection of moDCs with PRRSV and PCV2 resulted in an It has been suggested that moDCs infected by PRRSV were increased expression of PD-L1 (63), a molecule associated with able to induce the development of Tregs with suppressive activity negative regulation of T-cell stimulation (64). However, this in vitro (51, 52) and in vivo in the blood (52), lymphoid tissues effect was dependent on the PRRSV strain used. These (53), and lung (54). When the mononuclear cells isolated from results suggested that moDCs co-infected with PRRSV and blood and lung were restimulated ex vivo with PRRSV, TGF-b PCV2 could suppress the immune response and favor PCAVD and IL-10 were produced, suggesting that Tregs might play an pathogenesis (63). essential role in PRRSV immunopathogenesis. These Tregs seem to be induced mainly by PRRSV2 since studies using PRRSV1 failed to demonstrate the development of Tregs (33). The higher RESPONSE OF CONVENTIONAL DCs virulence of PRRSV2 isolates has been used to explain these AGAINST PRRSV differences (33). Other groups using moDCs infected with PRRSV1 or PRRV2 did not observe induction or proliferation One crucial question regarding PRRSV immunology is whether of Tregs (55). Moreover, Bordet et al. (29) did not observe IL-10 PRRSV infects, replicates, and modulates the response of cDCs. or TGF-b induced by highly virulent PRRSV1.3 Lena although According to the in vitro models using moDCs and bmDCs, the Tregs were not assessed (29). Also, Li and Mateu (56) did not immunopathology of PRRSV is due, at least partially, to the observe a significant proliferation of Tregs induced by in vitro infection of DCs. However, the few studies published dealing derived allogeneic PRRSV1-stimulated cDCs (56). Given the with bona fide cDCs isolated from pigs or used ex vivo showed a diversity of PRRSV, further studies are required to determine different picture. For example, Loving et al. (65), analyzing lung whether PRRSV1 differed from PRRSV2 in inducing Tregs. cDCs, concluded that PRRSV did not replicate in them (65). Interestingly, heat-inactivated PRRSV or pre-treated DCs with Using a similar strategy, Proll et al. (66) reported that DCs were IFN-a reduced the expansion of Tregs, indicating that viral susceptible to PRRSV1 infection and explained the discrepancy replication is probably necessary for Treg induction (51). of results as the type (PRRSV1 vs. PRRSV2) of virus used (66). The viral nucleocapsid protein (N) was presumed to be an Another explanation is the approach to get the DCs in both inducer of Tregs as transfection of moDCs with the N protein studies. The authors recovered DC by gradient centrifugation, induced an increase of Tregs and a comparable level of IL-10 in for which they had very heterogeneous populations that could PBMCs as the live virus-stimulated moDCs (57). Moreover, contain variable numbers of cDC and CD163pos cells in every neutralization of IL-10 in the cultures of transfected moDCs batch including macrophage-like cells. reduced the number of Tregs, reinforcing the notion that IL-10 Recently, other groups have evaluated the susceptibility of induction by N was responsible for the observed effect (58). bona fide cDCs to PRRSV infection, including PRRSV1, Frontiers in Immunology | www.frontiersin.org 3 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs PRRSV1.3, and PRRSV2. Resendiz et al. (67) described that (69). The number and the ratio of different types of cells could be tracheal bona fide cDCs, specifically cDC1 and cDC2, were not a reason for such differences. Taken together, cDCs are assumed susceptible to PRRSV2 infection but could modulate the to poorly participate in launching the adaptive immune response expression of cytokines and TLRs. In that study, tracheal against PRRSV, which, however, remains to be confirmed by explants were incubated with a PRRSV2 strain, and after 24 h further experiments. Interestingly, Li and Mateu (56) reported of culture, cells with the cDC1 and cCD2 phenotype were sorted. that sensing of PRRSV by cDC was enhanced when infected cells The results showed that cDC1 produced a high level of IFN-a, were used as a source of antigen and hypothesized that the meanwhile, cDC2 produced IL-10 and up-regulated the effective sensing of PRRSV by cDCs might not happen at the expression of TLR2 and TLR4. The authors proposed that early stage of infection (56). cDC1 and cDC2 actively participated in the immunopathology It is worth mentioning that virulence of PRRSV strains and of PRRSV infection (67). In parallel, Bordet et al. (29), interaction with DC seem to be related. Thus, while moderate demonstrated that ex vivo lung cDCs were also refractory to and low virulence strains might not activate cDCs, strains of PRRSV1.1 and PRRSV1.3 (Lena strain) infection and that cDC1 higher virulence, such as PRRSV1.3 Lena, induce a stronger Th1 and cDC2 had a differential response against PRRSV1.3. In the polarization and strongly upregulate several inflammatory, same study, the authors showed that lung cDC1 from PRRSV 1.3 interferon, and apoptosis pathways compared with the less Lena strain infected animals expressed mRNA of IFN-a, IL- virulent isolates (29, 70). Certainly, the accumulating evidence 12p35, IL-12p40, and TNF-a, while cDC2 expressed mRNA of suggests that this stronger regulation, particularly DCs, may play the regulatory TGF-b. In contrast, no cytokines were induced by a role in the immunopathology of those highly virulent strains. less virulent PRRSV1.1 strains Lelystad or FL13. To note, neither Lena nor the less virulent PRRSV1.1 strains induced an increase in the expression of the maturation markers MHC-I, MHC-II, CD80/86, or CD40. PLASMACYTOID DENDRITIC CELLS Recently, Li and Mateu (56), using in vitro derived cDCs, also AGAINTS PRRSV proved the non-susceptibility of cDC1 and cDC2. This work pDCs are highly specialized in producing large amounts of type I further revealed that cDC1 and cDC2 remained immature upon IFN in response to viral infection. A consensus has been reached PRRSV inoculation concerning the expression of maturation that pDCs are not susceptible to PRRSV (71–73). But the molecules, cytokine production, and the endocytosis/ production of type I IFN against PRRSV remains controversial. phagocytosis capabilities. These results contrast with some Calzada-Nova et al. (71) indicated that PRRSV did not induce previous studies that showed cytokine production after but inhibited IFN-a production in pDCs that were stimulated by inoculation by PRRSV (29, 68). The differences might be the TLR9 ligand. Later, Baumann et al. (72) evaluated different explained by different virus strains used. PRRSV1 and PRRSV2 strains and demonstrated that pDCs Puebla-Clark et al. (68), in experimental PRRSV2 infection, produced IFN-a in response to PRRSV and that only the showed that at 5- and 7-days post-infection, tonsil cDCs were highly virulent PRRSV2 strain inhibited IFN-a production negative for PRRSV as assessed by detection of PRRSV N protein. (72). In this case, discrepancies were explained by different Moreover, that study showed that at 5 days after infection cDCs approaches of separating pDCs. expressed IL-12 mRNA (68). Similar results were observed by Exposure of pDCs to PRRSV did not significantly inhibit the Parra-Sá nchez et al. (69) with sorted splenic DCs infected with natural capability of these cells to produce IFN-a except for some PRRSV2; they showed production of IL-12 evaluated by ELISA PRRSV2 strains, including the highly pathogenic PRRSV2 that (69). In summary, the current studies support the notion that emerged in China in 2006 and the highly virulent PRRSV1.3 cDCs are not susceptible to PRRSV infection but can differentially Lena strain. When pDCs were exposed to infected macrophages, respond to the virus. Probably, cDC1 showed a type 1 response the IFN-a production was higher than that obtained when using and cDC2 showed a type 2 pattern, but this needs to be confirmed cell-free virions (73), similar to what has been reported recently in further studies (Figure 1). Since the number of cDCs and the for cDCs (56). Efficient sensing of infected macrophages by pDCs ratio of cDC1/cDC2 vary between tissues, the immune response required integrin-mediated intercellular contact and intact actin launched in different tissues could be diversified and worth filaments in the macrophages (73). The potential contribution of further characterization. IFN-a to the immunity and immunopathology of PRRSV To what extent exposure of cDCs to PRRSV can affect the requires further in vivo studies. subsequent T-cell priming and proliferation? Preliminary results by Parra-Sá nchez et al. (69) showed that exposure to PRRSV2 did not affect the ability of cDCs to induce proliferation of CD3+ T cells, although co-culture with CD3+ T cells reduced the DC VACCINOLOGY: A STRATEGY TO production of IL-12 by cDCs (69). In contrast, CD163+ cells CONTROL PRRSV co-cultured with CD3+ T cells in the presence of PRRSV did not affect IL-12 production. It is worth mentioning that cDCs from Modulation of DC response is a field of continuous exploration, different tissues could respond differently. For example, blood and TLR is a widely studied area (74). The effects of TLR3 and cDC expressed higher IL-10 levels in comparison to spleen cDCs TLR7 ligands were assessed, individually or in combination, for Frontiers in Immunology | www.frontiersin.org 4 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs FIGURE 1 | Effects of PRRVS on different types of DCs. PRRSV can infect and replicate on moDCs, bmDCs and macrophages, increasing the expression and production of IL-10 while reducing IFN-a. In contrast, cDCs and pDCs are refractory to PRRSV infection but can respond with the production of cytokines, although the response could be dependent on the strain and the type of DCs. The figure shows the common patterns for PRRSV2 or virulent PRRSV1.3 as reported in the literature. their potential to improve the response of moDCs to an DC targeting is a promising approach to stimulate the inactivated PRRSV antigen (75). The results suggested that immune system in mice, humans, and animal species in the Th1 and Th2 responses were enhanced by TLR3 and TLR7 veterinary field (76). Recently two works described this strategy activation via TRIF/MYD88-NF-kB signaling pathway and, to modulate the immune response. Subramaniam et al. (77) therefore, these types of ligands might be new vaccine evaluated the targeting of three different receptors: DC-SIGN, candidates (75). However, the lack of inclusion of groups DEC205, and Langerin, using the ectodomain regions of where moDCs were stimulated with TLR ligands alone makes structural proteins of PRRSV (GP3, GP4, GP5, and M). The difficult to produce a definitive conclusion. In a study by Li and authors concluded that this approach did not induce protective Mateu (56) the authors showed that simultaneous addition of a immunity as viremia and lung lesions were not reduced in TLR7 ligand and PRRSV resulted in impaired response, treated groups (77). With a similar approach but using selected particularly in cytokine production. Therefore, the use of TLR7 peptides from structural and non-structural proteins of PRRSV, ligand as the adjuvant of PRRSV vaccines should be Bustamante-Có rdova et al. (78) obtained similar results. More further examined. studies are needed to identify if this strategy is suitable for Frontiers in Immunology | www.frontiersin.org 5 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs PRRSV in combination with the identification of more strain inhibited IFN-a release but less virulent strains induced immunogenic antigens, better immunization routes, and the release of this cytokine. Apart from the current observations, adjuvant combinations. some critical questions remain to be determined. How does the interaction of the virus with DCs interfere with the development of adaptive immune response? In detail, can cDCs and pDCs efficiently capture, process and, present PRRSV antigens? What CONCLUSIONS AND FURTHER is the mechanism and what are the receptors involved? Does the RESEARCH exposure to the virus (either live or inactivated) affect the antigen-presenting capabilities of DCs? Resolution of the role The current knowledge about PRRSV and its interaction with of DCs during PRRSV infection would be critical to producing porcine DCs is still scarce, but some concepts are consolidating. an effective vaccine. While bmDCs and moDCs may contain subsets of cells that support PRRSV replication (probably because of the expression of the viral receptor CD163), cDCs and pDCs seem not to be susceptible. When the response of cDCs and pDCs was examined AUTHOR CONTRIBUTIONS against different strains, the results were controversial. Using PRRSV2, cDC1 produced IL-12 and IFN-a, while cDC2 JH: conception. JH: writing original draft. YL and EM: writing, produced IL-10 and TGF-b. Using PRRSV1, low to moderate reviewing, and editing of the manuscript. All authors contributed virulence strains did not induce significant cytokine release in to the article and approved the submitted version. either cDC1 or cDC2 while the highly virulent Lena strain (PRRSV1.3.) induced IL-12-p40 expression in cDC1 and led to a Th1 polarization. Moreover, the distribution of cDC1 and FUNDING cDC2 in blood, lung and lymphoid tissues is different, and, accordingly, differences can be expected in those tissues. When This work was supported by the Consejo Nacional de Ciencia y pDC were examined, only again, the highly virulent PRRSV2 Tecnologı́a (CONACyT), grant number 222973. REFERENCES 10. Wang Yx, Zhou Yj, Li Gx, Zhang Sr, Jiang Yf, Xu At, et al. Identification of Immunodominant T-Cell Epitopes in Membrane Protein of Highly 1. Collins JE, Benfield DA, Christianson WT, Harris L, Hennings JC, Shaw DP, Pathogenic Porcine Reproductive and Respiratory Syndrome Virus. Virus et al. Isolation of Swine Infertility and Respiratory Syndrome Virus (Isolate Res (2011) 158:108–15. doi: 10.1016/j.virusres.2011.03.018 ATCC VR-2332) in North America and Experimental Reproduction of the 11. Parida R, Choi IS, Peterson DA, Pattnaik AK, Laegreid W, Zuckermann FA, Disease in Gnotobiotic Pigs. J Vet Diagn Investig (1992) 4:117–26. et al. Location of T-Cell Epitopes in Nonstructural Proteins 9 and 10 of Type- doi: 10.1177/104063879200400201 II Porcine Reproductive and Respiratory Syndrome Virus. Virus Res (2012) 2. Holtkamp DJ, Kliebenstein JB, Neumann EJ, Zimmerman JJ, Rotto HF, Yoder 169:13–21. doi: 10.1016/j.virusres.2012.06.024 TK, et al. Assessment of the Economic Impact of Porcine Reproductive and 12. Burgara-Estrella A, Dı́az I, Rodrı́guez-Gó mez IM, Essler SE, Herná ndez J, Respiratory Syndrome Virus on United States Pork Producers. J Swine Heal Mateu E. Predicted Peptides From Non-Structural Proteins of Porcine Prod (2013) 21:72–84. doi: 10.31274/ans_air-180814-28 Reproductive and Respiratory Syndrome Virus Are Able to Induce IFN-g 3. Adams MJ, Lefkowitz EJ, King AMQ, Harrach B, Harrison RL, Knowles NJ, and IL-10. Viruses (2013) 5:663–77. doi: 10.3390/v5020663 et al. Changes to Taxonomy and the International Code of Virus 13. Steinman RM. The Dendritic Cell System and its Role in Immunogenicity. Annu Classification and Nomenclature Ratified by the International Committee Rev Immunol (1991) 9:271–96. doi: 10.1146/annurev.iy.09.040191.001415 on Taxonomy of Viruses (2017). Arch Virol (2017) 162:2505–38. doi: 10.1007/ 14. Mellman I, Steinman RM. Dendritic Cells: Specialized and Regulated Antigen s00705-017-3358-5 Processing Machines. Cell (2001) 106:255–8. doi: 10.1016/S0092-8674(01) 4. Snijder EJ, Kikkert M, Fang Y. Arterivirus Molecular Biology and 00449-4 Pathogenesis. J Gen Virol (2013) 94:2141–63. doi: 10.1099/vir.0.056341-0 15. Schlitzer A, Sivakamasundari V, Chen J, Sumatoh HRB, Schreuder J, Lum J, 5. Rascó n-Castelo E, Burgara-Estrella A, Mateu E, Herná ndez J. Immunological et al. Identification of Cdc1- and Cdc2-Committed DC Progenitors Reveals Features of the non-Structural Proteins of Porcine Reproductive and Early Lineage Priming at the Common DC Progenitor Stage in the Bone Respiratory Syndrome Virus. Viruses (2015) 7:873–86. doi: 10.3390/v7030873 Marrow. Nat Immunol (2015) 16:718–28. doi: 10.1038/ni.3200 6. Loving CL, Osorio FA, Murtaugh MP, Zuckermann FA. Innate and Adaptive 16. Villadangos JA, Young L. Antigen-Presentation Properties of Plasmacytoid Immunity Against Porcine Reproductive and Respiratory Syndrome Virus. Vet Dendritic Cells. Immunity (2008) 29:352–61. doi: 10.1016/j.immuni. Immunol Immunopathol (2015) 167:1–14. doi: 10.1016/j.vetimm.2015.07.003 2008.09.002 7. Meier WA, Galeota J, Osorio FA, Husmann RJ, Schnitzlein WM, Zuckermann FA. 17. Haniffa M, Shin A, Bigley V, McGovern N, Teo P, See P, et al. Human Tissues Gradual Development of the Interferon-g Response of Swine to Porcine Contain CD141 Hi Cross-Presenting Dendritic Cells With Functional Reproductive and Respiratory Syndrome Virus Infection or Vaccination. Homology to Mouse CD103 + Nonlymphoid Dendritic Cells. Immunity Virology (2003) 309:18–31. doi: 10.1016/S0042-6822(03)00009-6 (2012) 37:60–73. doi: 10.1016/j.immuni.2012.04.012 8. Van Breedam W, Delputte PL, Van Gorp H, Misinzo G, Vanderheijden N, Duan 18. Schlitzer A, Ginhoux F. Organization of the Mouse and Human DC Network. X, et al. Porcine Reproductive and Respiratory Syndrome Virus Entry Into the Curr Opin Immunol (2014) 26:90–9. doi: 10.1016/j.coi.2013.11.002 Porcine Macrophage. J Gen Virol (2010) 91:1659–67. doi: 10.1099/vir.0.020503-0 19. Schlitzer A, McGovern N, Ginhoux F. Dendritic Cells and Monocyte-Derived 9. Dı́az I, Darwich L, Pappaterra G, Pujols J, Mateu E. Immune Responses of Cells: Two Complementary and Integrated Functional Systems. Semin Cell Pigs After Experimental Infection With a European Strain of Porcine Dev Biol (2015) 41:9–22. doi: 10.1016/j.semcdb.2015.03.011 Reproductive and Respiratory Syndrome Virus. J Gen Virol (2005) 20. Franzoni G, Graham SP, Giudici SD, Oggiano A. Porcine Dendritic Cells and 86:1943–51. doi: 10.1099/vir.0.80959-0 Viruses: An Update. Viruses (2019) 11:445. doi: 10.3390/v11050445 Frontiers in Immunology | www.frontiersin.org 6 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs 21. Guilliams M, Dutertre CA, Scott CL, McGovern N, Sichien D, Chakarov S, Response to Streptococcus Suis Infection Reveals Up-Regulation of et al. Unsupervised High-Dimensional Analysis Aligns Dendritic Cells Across Inflammatory-Related Genes Expression. PloS One (2016) 11:e0156019. Tissues and Species. Immunity (2016) 45:669–84. doi: 10.1016/ doi: 10.1371/journal.pone.0156019 j.immuni.2016.08.015 38. Singleton H, Graham SP, Bodman-Smith KB, Frossard JP, Steinbach F. 22. Auray G, Keller I, Python S, Gerber M, Bruggmann R, Ruggli N, et al. Establishing Porcine Monocyte-Derived Macrophage and Dendritic Cell Characterization and Transcriptomic Analysis of Porcine Blood Conventional Systems for Studying the Interaction With PRRSV-1. Front Microbiol and Plasmacytoid Dendritic Cells Reveals Striking Species-Specific (2016) 7:832. doi: 10.3389/fmicb.2016.00832 Differences. J Immunol (2016) 197:4791–806. doi: 10.4049/jimmunol.1600672 39. Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone 23. Edwards JC, Everett HE, Pedrera M, Mokhtar H, Marchi E, Soldevila F, et al. MBA. Interleukin-10 Determines Viral Clearance or Persistence In Vivo. Nat CD1- and CD1+ Porcine Blood Dendritic Cells are Enriched for the Med (2006) 12:1301–9. doi: 10.1038/nm1492 Orthologues of the Two Major Mammalian Conventional Subsets. Sci Rep 40. Liu X, Fan B, Bai J, Wang H, Li Y, Jiang P. The N-N non-Covalent Domain of (2017) 7:40942. doi: 10.1038/srep40942 the Nucleocapsid Protein of Type 2 Porcine Reproductive and Respiratory 24. Parra-Sá nchez H, Puebla-Clark L, Resé ndiz M, Valenzuela O, Herná ndez J. Syndrome Virus Enhances Induction of IL-10 Expression. J Gen Virol (2015) Characterization and Expression of DEC205 in the Cdc1 and Cdc2 Subsets of 96:1276–86. doi: 10.1099/vir.0.000061 Porcine Dendritic Cells From Spleen, Tonsil, and Submaxillary and 41. Peng Y-T, Chaung H-C, Chang H-L, Chang H-C, Chung W-B. Modulations Mesenteric Lymph Nodes. Mol Immunol (2018) 96:1–7. doi: 10.1016/ of Phenotype and Cytokine Expression of Porcine Bone Marrow-Derived j.molimm.2018.02.003 Dendritic Cells by Porcine Reproductive and Respiratory Syndrome Virus. 25. Soldevila F, Edwards JC, Graham SP, Stevens LM, Crudgington B, Crooke HR, Vet Microbiol (2009) 136:359–65. doi: 10.1016/j.vetmic.2008.11.013 et al. Characterization of the Myeloid Cell Populations’ Resident in the 42. Chaung HC, Chen CW, Hsieh BL, Chung WB. Toll-Like Receptor Porcine Palatine Tonsil. Front Immunol (2018) 9:1800. doi: 10.3389/ Expressions in Porcine Alveolar Macrophages and Dendritic Cells in fimmu.2018.01800 Responding to Poly IC Stimulation and Porcine Reproductive and 26. Marquet F, Bonneau M, Pascale F, Urien C, Kang C, Schwartz-Cornil I, et al. Respiratory Syndrome Virus (PRRSV) Infection. Comp Immunol Microbiol Characterization of Dendritic Cells Subpopulations in Skin and Afferent Infect Dis (2010) 33:197–213. doi: 10.1016/j.cimid.2008.10.001 Lymph in the Swine Model. PloS One (2011) 6:e16320. doi: 10.1371/ 43. Subramaniam S, Sur JH, Kwon B, Pattnaik AK, Osorio FA. A Virulent Strain journal.pone.0016320 of Porcine Reproductive and Respiratory Syndrome Virus Does Not Up- 27. Maisonnasse P, Bouguyon E, Piton G, Ezquerra A, Urien C, Deloizy C, et al. Regulate Interleukin-10 Levels In Vitro or In Vivo. Virus Res (2011) 155:415– The Respiratory DC/Macrophage Network at Steady-State and Upon 22. doi: 10.1016/j.virusres.2010.11.010 Influenza Infection in the Swine Biomedical Model. Mucosal Immunol 44. Gimeno M, Darwich L, Diaz I, de la Torre E, Pujols J, Martı́n M, et al. (2016) 9:835–49. doi: 10.1038/mi.2015.105 Cytokine Profiles and Phenotype Regulation of Antigen Presenting Cells by 28. Qu C, Brinck-Jensen NS, Zang M, Chen K. Monocyte-Derived Dendritic Genotype-I Porcine Reproductive and Respiratory Syndrome Virus Isolates. Cells: Targets as Potent Antigen-Presenting Cells for the Design of Vaccines Vet Res (2011) 42:9. doi: 10.1186/1297-9716-42-9 Against Infectious Diseases. Int J Infect Dis (2014) 19:1–5. doi: 10.1016/ 45. Weesendorp E, Stockhofe-Zurwieden N, Popma-De Graaf DJ, Fijten H, Rebel j.ijid.2013.09.023 JMJ. Phenotypic Modulation and Cytokine Profiles of Antigen Presenting 29. Bordet E, Blanc F, Tiret M, Crisci E, Bouguyon E, Renson P, et al. Porcine Cells by European Subtype 1 and 3 Porcine Reproductive and Respiratory Reproductive and Respiratory Syndrome Virus Type 1.3 Lena Triggers Syndrome Virus Strains In Vitro and In Vivo. Vet Microbiol (2013) 167:638– Conventional Dendritic Cells 1 Activation and T Helper 1 Immune 50. doi: 10.1016/j.vetmic.2013.09.021 Response Without Infecting Dendritic Cells. Front Immunol (2018) 9:2299. 46. Cecere TE, Meng XJ, Pelzer K, Todd SM, Beach NM, Ni YY, et al. Co- doi: 10.3389/fimmu.2018.02299 Infection of Porcine Dendritic Cells With Porcine Circovirus Type 2a 30. Wang X, Eaton M, Mayer M, Li H, He D, Nelson E, et al. Porcine (PCV2a) and Genotype II Porcine Reproductive and Respiratory Syndrome Reproductive and Respiratory Syndrome Virus Productively Infects Virus (PRRSV) Induces CD4+CD25+FoxP3+ T Cells In Vitro. Vet Microbiol Monocyte-Derived Dendritic Cells and Compromises Their Antigen- (2012) 160:233–9. doi: 10.1016/j.vetmic.2012.04.040 Presenting Ability. Arch Virol (2007) 152:289–303. doi: 10.1007/s00705- 47. Gó mez-Laguna J, Salguero FJ, Barranco I, Pallaré s FJ, Rodrı́guez-Gó mez IM, 006-0857-1 Bernabé A, et al. Cytokine Expression by Macrophages in the Lung of Pigs 31. Flores-Mendoza L, Silva-Campa E, Resé ndiz M, Osorio FA, Herná ndez J. Infected With the Porcine Reproductive and Respiratory Syndrome Virus. Porcine Reproductive and Respiratory Syndrome Virus Infects Mature J Comp Pathol (2010) 142:51–60. doi: 10.1016/j.jcpa.2009.07.004 Porcine Dendritic Cells and Up-Regulates Interleukin-10 Production. Clin 48. Maizels RM, Smith KA. Regulatory T Cells in Infection. In: . Advances in Vaccine Immunol (2008) 15:720–5. doi: 10.1128/CVI.00224-07 Immunology (2011) 112:73–136. doi: 10.1016/B978-0-12-387827-4.00003-6 32. Park JY, Kim HS, Seo SH. Characterization of Interaction Between Porcine 49. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of Immune Reproductive and Respiratory Syndrome Virus and Porcine Dendritic Cells. Suppression by Interleukin-10 and Transforming Growth Factor-b: The Role J Microbiol Biotechnol (2008) 18:1709–16. of T Regulatory Cells. Immunology (2006) 117:433–42. doi: 10.1111/j.1365- 33. Silva-Campa E, Cordoba L, Fraile L, Flores-Mendoza L, Montoya M, 2567.2006.02321.x Herná ndez J. European Genotype of Porcine Reproductive and Respiratory 50. Zhao H, Liao X, Kang Y. Tregs: Where We are and What Comes Next? Front Syndrome (PRRSV) Infects Monocyte-Derived Dendritic Cells But Does Not Immunol (2017) 8:1578. doi: 10.3389/fimmu.2017.01578 Induce Treg Cells. Virology (2010) 396:264–71. doi: 10.1016/ 51. Silva-Campa E, Flores-Mendoza L, Resé ndiz M, Pinelli-Saavedra A, Mata- j.virol.2009.10.024 Haro V, Mwangi W, et al. Induction of T Helper 3 Regulatory Cells by 34. Sang Y, Rowland RRR, Blecha F. Antiviral Regulation in Porcine Monocytic Dendritic Cells Infected With Porcine Reproductive and Respiratory Cells at Different Activation States. J Virol (2014) 88:1395–410. doi: 10.1128/ Syndrome Virus. Virology (2009) 387:373–9. doi: 10.1016/j.virol.2009.02.033 jvi.01714-14 52. Wongyanin P, Buranapraditkun S, Chokeshai-usaha K, Thanawonguwech R, 35. Chang H-C, Peng Y-T, Chang H, Chaung H-C, Chung W-B. Phenotypic and Suradhat S. Induction of Inducible CD4+CD25+Foxp3+ Regulatory T Functional Modulation of Bone Marrow-Derived Dendritic Cells by Porcine Lymphocytes by Porcine Reproductive and Respiratory Syndrome Virus Reproductive and Respiratory Syndrome Virus. Vet Microbiol (2008) (PRRSV). Vet Immunol Immunopathol (2010) 133:170–82. doi: 10.1016/ 129:281–93. doi: 10.1016/j.vetmic.2007.12.002 j.vetimm.2009.07.012 36. Liu J, Wei S, Liu L, Shan F, Zhao Y, Shen G. The Role of Porcine Reproductive 53. Silva-Campa E, Mata-Haro V, Mateu E, Herná ndez J. Porcine Reproductive and Respiratory Syndrome Virus Infection in Immune Phenotype and Th1/ and Respiratory Syndrome Virus Induces CD4 +CD8 +CD25 +Foxp3 + Th2 Balance of Dendritic Cells. Dev Comp Immunol (2016) 65:245–52. Regulatory T Cells (Tregs). Virology (2012) 430:73–80. doi: 10.1016/ doi: 10.1016/j.dci.2016.07.012 j.virol.2012.04.009 37. Auray G, Lachance C, Wang Y, Gagnon CA, Segura M, Gottschalk M. 54. Nedumpun T, Sirisereewan C, Thanmuan C, Techapongtada P, Transcriptional Analysis of PRRSV-Infected Porcine Dendritic Cell Puntarotairung R, Naraprasertkul S, et al. Induction of Porcine Frontiers in Immunology | www.frontiersin.org 7 July 2021 | Volume 12 | Article 712109 Hernández et al. Effects of PRRSV on DCs Reproductive and Respiratory Syndrome Virus (PRRSV)-Specific Regulatory 69. Parra-Sá nchez H, Bustamante-Có rdova L, Resé ndiz M, Mata-Haro V, Pinelli- T Lymphocytes (Treg) in the Lungs and Tracheobronchial Lymph Nodes of Saavedra A, Herná ndez J. Analysis of Swine Conventional Dendritic Cells, PRRSV-Infected Pigs. Vet Microbiol (2018) 216:13–9. doi: 10.1016/ DEC205+CD172A+/-CADM1+, From Blood and Spleen in Response to j.vetmic.2018.01.014 PRRSV and PEDV. Viruses (2019) 11:1001. doi: 10.3390/v11111004 55. Rodrı́guez-Gó mez IM, Käser T, Gó mez-Laguna J, Lamp B, Sinn L, Rümenapf T, 70. Crisci E, Moroldo M, Vu Manh TP, Mohammad A, Jourdren L, Urien C, et al. et al. PRRSV-Infected Monocyte-Derived Dendritic Cells Express High Levels of Distinctive Cellular and Metabolic Reprogramming in Porcine Lung SLA-DR and CD80/86 But Do Not Stimulate PRRSV-Naïve Regulatory T Cells Mononuclear Phagocytes Infected With Type 1 PRRSV Strains. Front to Proliferate. Vet Res (2015) 46:54. doi: 10.1186/s13567-015-0186-z Immunol (2020) 11:588411. doi: 10.3389/fimmu.2020.588411 56. Li Y, Mateu E. Interaction of Type 1 Porcine Reproductive and Respiratory 71. Calzada-Nova G, Schnitzlein W, Husmann R, Zuckermann FA. Syndrome Virus With In Vitro Derived Conventional Dendritic Cells. Front Characterization of the Cytokine and Maturation Responses of Pure Immunol (2021) 12:674185. doi: 10.3389/fimmu.2021.674185 Populations of Porcine Plasmacytoid Dendritic Cells to Porcine Viruses 57. Fan B, Liu X, Bai J, Li Y, Zhang Q, Jiang P. The 15N and 46R Residues of and Toll-Like Receptor Agonists. Vet Immunol Immunopathol (2010) Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus 135:20–33. doi: 10.1016/j.vetimm.2009.10.026 Nucleocapsid Protein Enhance Regulatory T Lymphocytes Proliferation. PloS 72. Baumann A, Mateu E, Murtaugh MP, Summerfield A. Impact of Genotype 1 One (2015) 10:e0138772. doi: 10.1371/journal.pone.0138772 and 2 of Porcine Reproductive and Respiratory Syndrome Viruses on 58. Wongyanin P, Buranapraditkul S, Yoo D, Thanawongnuwech R, Roth JA, Interferon-a Responses by Plasmacytoid Dendritic Cells. Vet Res (2013) Suradhat S. Role of Porcine Reproductive and Respiratory Syndrome Virus 44:33. doi: 10.1186/1297-9716-44-33 Nucleocapsid Protein in Induction of Interleukin-10 and Regulatory T- 73. Garcı́a-Nicolá s O, Auray G, Sautter CA, Rappe JCF, McCullough KC, Ruggli Lymphocytes (Treg). J Gen Virol (2012) 93:1236–46. doi: 10.1099/vir.0.040287-0 N, et al. Sensing of Porcine Reproductive and Respiratory Syndrome Virus- 59. Nedumpun T, Wongyanin P, Sirisereewan C, Ritprajak P, Palaga T, Infected Macrophages by Plasmacytoid Dendritic Cells. Front Microbiol Thanawongnuwech R, et al. Interleukin-1 Receptor Antagonist: An Early (2016) 7:771. doi: 10.3389/fmicb.2016.00771 Immunomodulatory Cytokine Induced by Porcine Reproductive and 74. Ferná ndez A, Oliver L, Alvarez R, Ferná ndez LE, Lee KP, Mesa C. Adjuvants Respiratory Syndrome Virus. J Gen Virol (2017) 98:77–88. doi: 10.1099/ and Myeloid-Derived Suppressor Cells: Enemies or Allies in Therapeutic jgv.0.000665 Cancer Vaccination. Hum Vaccines Immunother (2014) 10:3251–60. 60. Nedumpun T, Techakriengkrai N, Thanawongnuwech R, Suradhat S. doi: 10.4161/hv.29847 Negative Immunomodulatory Effects of Type 2 Porcine Reproductive and 75. Hu Y, Cong X, Chen L, Qi J, Wu X, Zhou M, et al. Synergy of TLR3 and 7 Respiratory Syndrome Virus-Induced Interleukin-1 Receptor Antagonist on Ligands Significantly Enhances Function of DCs to Present Inactivated Porcine Innate and Adaptive Immune Functions. Front Immunol (2019) PRRSV Antigen Through TRIF/MyD88-NF-kb Signaling Pathway. Sci Rep 10:579. doi: 10.3389/fimmu.2019.00579 (2016) 6:23977. doi: 10.1038/srep23977 61. Chen W-Y, Schniztlein WM, Calzada-Nova G, Zuckermann FA. Genotype 2 76. Alvarez B, Poderoso T, Alonso F, Ezquerra A, Domı́nguez J, Revilla C. Strains of Porcine Reproductive and Respiratory Syndrome Virus Dysregulate Antigen Targeting to APC: From Mice to Veterinary Species. Dev Comp Alveolar Macrophage Cytokine Production via the Unfolded Protein Immunol (2013) 41:153–63. doi: 10.1016/j.dci.2013.04.021 Response. J Virol (2017) 92:e01251–17. doi: 10.1128/jvi.01251-17 77. Subramaniam S, Piñeyro P, Derscheid RJ, Madson DM, Magstadt DR, Meng 62. Lechmann M, Berchtold S, Steinkasserer A, Hauber J. CD83 on Dendritic XJ. Dendritic Cell-Targeted Porcine Reproductive and Respiratory Syndrome Cells: More Than Just a Marker for Maturation. Trends Immunol (2002) Virus (PRRSV) Antigens Adjuvanted With Polyinosinic-Polycytidylic Acid 23:273–5. doi: 10.1016/S1471-4906(02)02214-7 (Poly (I:C)) Induced Non-Protective Immune Responses Against 63. Richmond O, Cecere TE, Erdogan E, Meng XJ, Piñeyro P, Subramaniam S, et al. Heterologous Type 2 PRRSV Challenge in Pigs. Vet Immunol The PD-L1/CD86 Ratio is Increased in Dendritic Cells Co-Infected With Porcine Immunopathol (2017) 190:18–25. doi: 10.1016/j.vetimm.2017.07.003 Circovirus Type 2 and Porcine Reproductive and Respiratory Syndrome Virus, 78. Bustamante-Có rdova L, Resé ndiz-Sandoval M, Herná ndez J. Evaluation of a and the PD-L1/PD-1 Axis Is Associated With Anergy, Apoptosis, and the Recombinant Mouse X Pig Chimeric Anti-Porcine DEC205 Antibody Fused Induction of Regulatory T-Cells in Porcine Lymphocytes. Vet Microbiol (2015) With Structural and Nonstructural Peptides of PRRS Virus. Vaccines (2019) 180:223–9. doi: 10.1016/j.vetmic.2015.09.014 7:43. doi: 10.3390/vaccines7020043 64. Mizuno R, Sugiura D, Shimizu K, Maruhashi T, Watada M, Okazaki I, et al. PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Conflict of Interest: The authors declare that the research was conducted in the Activation. Front Immunol (2019) 10:630. doi: 10.3389/fimmu.2019.00630 absence of any commercial or financial relationships that could be construed as a 65. Loving CL, Brockmeier SL, Sacco RE. Differential Type I Interferon Activation potential conflict of interest. and Susceptibility of Dendritic Cell Populations to Porcine Arterivirus. Immunology (2007) 120:217–29. doi: 10.1111/j.1365-2567.2006.02493.x Publisher’s Note: All claims expressed in this article are solely those of the authors 66. Pröll MJ, Neuhoff C, Schellander K, Uddin MJ, Cinar MU, Sahadevan S, et al. and do not necessarily represent those of their affiliated organizations, or those of Transcriptome Profile of Lung Dendritic Cells After In Vitro Porcine the publisher, the editors and the reviewers. Any product that may be evaluated in Reproductive and Respiratory Syndrome Virus (PRRSV) Infection. PloS this article, or claim that may be made by its manufacturer, is not guaranteed or One (2017) 12:e0187735. doi: 10.1371/journal.pone.0187735 endorsed by the publisher. 67. Reséndiz M, Valenzuela O, Hernández J. Response of the Cdc1 and Cdc2 Subtypes of Tracheal Dendritic Cells to Porcine Reproductive and Respiratory Syndrome Copyright © 2021 Hernań dez, Li and Mateu. This is an open-access article distributed Virus. Vet Microbiol (2018) 223:27–33. doi: 10.1016/j.vetmic.2018.07.012 under the terms of the Creative Commons Attribution License (CC BY). The use, 68. Puebla-Clark L, Parra-Sá nchez H, Resé ndiz M, Valenzuela O, Herná ndez J. distribution or reproduction in other forums is permitted, provided the original author(s) Tonsil Conventional Dendritic Cells Are Not Infected by Porcine Reproductive and the copyright owner(s) are credited and that the original publication in this journal is and Respiratory Syndrome Virus. Virology (2019) 529:65–72. doi: 10.1016/ cited, in accordance with accepted academic practice. No use, distribution or j.virol.2019.01.012 reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 8 July 2021 | Volume 12 | Article 712109