MINI REVIEW published: 29 October 2021 doi: 10.3389/fmed.2021.731911 Human CLA+ Memory T Cell and Cytokines in Psoriasis Carmen de Jesús-Gil 1 , Lídia Sans-de San Nicolàs 1 , Irene García-Jiménez 1 , Marta Ferran 2 , Ramon M. Pujol 2 and Luis F. Santamaria-Babí 1* 1 Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Parc Científic de Barcelona, Barcelona, Spain, 2 Department of Dermatology, Hospital del Mar (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autònoma de Barcelona, Barcelona, Spain Psoriasis is a common inflammatory skin condition resulting from the interplay between epidermal keratinocytes and immunological cellular components. This sustained inflammation is essentially driven by pro-inflammatory cytokines with the IL-23/IL-17 axis playing a critical central role, as proved by the clinical efficacy of their blockade in patients. Among all the CD45R0+ memory T cell subsets, those with special tropism for cutaneous tissues are identified by the expression of the Cutaneous Lymphocyte-associated Antigen (CLA) carbohydrate on their surface, that is induced during T cell maturation particularly in the skin-draining lymph nodes. Because of their ability to recirculate Edited by: between the skin and blood, circulating CLA+ memory T cells reflect the immune Paul Smith, Connect Biopharma, United States abnormalities found in different human cutaneous conditions, such as psoriasis. Based Reviewed by: on this premise, studying the effect of different environmental microbial triggers and Marina Venturini, psoriatic lesional cytokines on CLA+ memory T cells, in the presence of autologous Civil Hospital of Brescia, Italy epidermal cells from patients, revealed important IL-17 cytokines responses that are likely Eva Reali, University of Milano-Bicocca, Italy to enhance the pro-inflammatory loop underlying the development of psoriatic lesions. *Correspondence: The goal of this mini-review is to present latest data regarding cytokines implicated in Luis F. Santamaria-Babí plaque and guttate psoriasis immunopathogenesis from the prism of CLA+ memory T luis.santamaria@ub.edu cells, that are specifically related to the cutaneous immune system. Specialty section: Keywords: psoriasis, CLA+ T cell, IL17A, interleukins, IL17F, IL-9, IL-15 This article was submitted to Dermatology, a section of the journal Frontiers in Medicine INTRODUCTION Received: 28 June 2021 The regulation of cytokine production and signaling in chronic cutaneous inflammation is Accepted: 08 October 2021 influenced by genetic and environmental factors. This minireview focuses on human psoriasis, both Published: 29 October 2021 plaque and guttate forms of the disease, and the cytokine production by human circulating CLA+ Citation: memory T cells, a relevant subset of memory T cells associated to the regional cutaneous immune de Jesús-Gil C, Sans-de San system. In translational research in dermatology, there is a need to develop new approaches beyond Nicolàs L, García-Jiménez I, Ferran M, animal models and in vitro studies (1, 2), since the results in those models are not always translated Pujol RM and Santamaria-Babí LF (2021) Human CLA+ Memory T Cell into the clinic (3). For instance, excellent basic science results in the field of cytokines in psoriasis and Cytokines in Psoriasis. have been generated for IFN-α, IFN-γ, IL-20, or IL-22, but their in vivo neutralization with Front. Med. 8:731911. monoclonal antibodies in clinical trials did not improve psoriasis severity (4–7), indicating that doi: 10.3389/fmed.2021.731911 those cytokines, despite their presence in the lesions, are not suitable for patients’ treatment. Frontiers in Medicine | www.frontiersin.org 1 October 2021 | Volume 8 | Article 731911 de Jesús-Gil et al. Cytokines and CLA+ T Cells in Psoriasis When studying human chronic cutaneous inflammatory T cells-dependent IL-17A, IFN-γ, and IL-22 production are diseases, an alternative approach focused on the human regional directly associated shows how these cytokines can be measured cutaneous immune system in disease would allow to focus ex vivo and integrated with the patient clinical features and more closely on the immunological mechanism of disease environmental exposure to S. pyogenes. that takes place within the skin, the proper organ where In the following subsections, information on cytokines in the pathological process is carried out. The presence of the psoriasis immunopathology is provided from the prism of T skin associated lymphoid tissue (SALT) was proposed by J. cells that are related to the cutaneous immune system. These Wayne Streilein based on the existence of some T cells with results have been generated using clinical material (blood and special function related only to the skin (8). The Cutaneous skin biopsies) from non-treated psoriasis patients. Lymphocyte-associated Antigen (CLA) identifies the subset of effector memory T cells with skin tropism that recirculates INFLUENCE OF PSORIATIC between skin and blood during cutaneous inflammation and INFLAMMATORY ENVIRONMENT ON reflects immunological abnormalities present in the skin. The CLA molecule is a carbohydrate modification of the platelet CLA-DEPENDENT IL-17A AND IL-17F selectin ligand-1 (PSGL-1) (9), which binds both endothelial PRODUCTION cell and platelet selectins (E-selectin and P-selectin) molecules expressed on post-capillary venules in the skin. Its expression is Memory T cells present in the psoriatic lesion are exposed to induced on CD45R0+ memory T cells at skin draining lymph the cytokine inflammatory environment and this may influence nodes (10) and it is present in more than 90% of cutaneous the effector functions of the IL-17 cytokines, that are clinically infiltrating T cells but in <20% of T cells in other peripheral relevant mediators in psoriasis. Since peripheral CLA+ memory tissues. Interestingly, a proportion of CLA-expressing T cells T cells recirculate between skin and blood during psoriasis and can be also found in circulation, representing around 15% of reflect the immunological abnormalities present in the skin, they human circulating T cells (10). Indeed, the fact that CLA+ can be used to study the lesional inflammatory environmental memory T cells recirculate between skin and blood was evidenced cytokines. The presence of IL-15 and IL-23 is increased in lesional by action of efalizumab (a monoclonal antibody targeting the skin from psoriasis patients. Psoriatic epidermal keratinocytes CD11a subunit of LFA-1 molecule that blocked lymphocyte show increased expression of both IL-15 and IL-15R (17). extravasation toward the skin) in psoriasis (11) and atopic Similarly, injured keratinocytes but also dendritic cells have dermatitis (12) patients, which proved clinical improvement been proved to produce increased amounts of IL-23 in psoriatic but also resulted in a lymphocytosis effect of CLA+ T cells lesions (18). Besides, both pro-inflammatory cytokines are linked that caused relapses after treatment discontinuation (13). The to Th17 biology. IL-15 is known to induce IL-17 secretion recirculating capacity of CLA+ memory T cells is key to their by T cells and to be critical for maintaining memory Th17 value in translational research, due to their ability to reflect the cells (19), whilst IL-23 is considered the “master regulator” of immune abnormalities found in numerous human cutaneous Th17 cell differentiation and development. Single nucleotide conditions such as psoriasis, atopic dermatitis, contact dermatitis, polymorphisms (SNPs) associated with psoriasis have been also drug-induced allergic reactions, vitiligo, herpes simplex, rosacea, described for both IL-15 and IL-23 (20–22). However, despite cutaneous T cell lymphoma, or alopecia areata (14, 15). their known connection to psoriasis pathogenesis, it was not In order to properly study the regional cutaneous immune until recently that the cooperation between these two cytokines system in psoriasis, the use of clinical material from non- has been addressed. Our group has shown that IL-15 and IL- treated patients provides clear advantages as it is commented 23 act synergistically on cocultures of CLA+ memory T cells below. With this purpose, we have established a new ex vivo and autologous epidermal cells to produce significantly increased coculture model made of lymphoid and epidermal cells from the levels of IL-17F and IL-17A in psoriasis when compared to same patient (16) that integrates relevant elements of psoriasis CLA− T cells cocultures (23). Importantly, this synergy was immunopathology: skin-associated memory T cells (CLA+ T not observed for lesional resident memory T cells or in cells) isolated from blood samples, autologous lesional epidermal cocultures from healthy individuals, pointing out the relevance of cells disaggregated from biopsies from the same patient and circulating CLA+ T cells in psoriasis pathogenesis. Altogether, it a clinically relevant trigger of the disease and flares (such as is a clear example of how the proinflammatory milieu in psoriatic Streptococcus pyogenes). When circulating CLA+ T cells and lesions influences specifically skin-tropic memory T cells and autologous lesional epidermal cells cocultures are activated by induces a Th17 response contributing to the maintenance of Streptococcus pyogenes extract (SE), specific Th17/Th1/Th22 the disease. responses occurs, together with production of disease relevant chemokines (CXCL9, CXCL10, CXCL11), which is not the case CLA+ T CELLS IN PSORIASIS PRODUCE in CLA− T cells cocultures or in unstimulated basal conditions. MORE IL-17F THAN IL-17A Interestingly, the levels of IL-17A and other cytokines expressed by CLA+ T cells in response to SE are highly correlated The IL-17 family comprises six structurally related members with serum anti-Streptolysin O antibody titer (ASO), that is (named from A to F) that act as homodimers, except for commonly used to assess patients recent infection by S. pyogenes IL-17A and IL-17F that can form heterodimers together. In in daily clinical practice. The fact that ASO levels and CLA+ psoriasis, IL-17A is pointed out as the most important mediator Frontiers in Medicine | www.frontiersin.org 2 October 2021 | Volume 8 | Article 731911 de Jesús-Gil et al. Cytokines and CLA+ T Cells in Psoriasis (24), which is supported by the effectiveness of its blockade T cells, as well as it promoted the survival of the skin-homing T in patients. However, its principal homolog, IL-17F, has been cell subset in psoriasis. also proved to be increased in lesional skin and blood from Using well-defined clinical samples also allows obtaining psoriasis patients (25–27). From our experience, circulating information on the relationship of cytokines with patient CLA+ memory T cells activated with a relevant disease trigger, clinical status. CLA+ T cells-derived cytokines are associated such as Streptococcus pyogenes, and in the presence of lesional with clinical features of skin diseases because they represent epidermal cells, secrete a higher amount of IL-17F than IL- a subset of memory T cells that are involved in the regional 17A in vitro (28, 29). Similarly, increased CLA+ memory T cutaneous immune system. To support the relevance of our cell-dependent IL-17F response was observed when stimulating findings regarding the role of IL-9 in psoriasis, it was observed the cocultures with Candida albicans (30) or the combination that SE-induced CLA+ T cells-dependent IL-9 correlated with of the pro-inflammatory cytokines IL-15 and IL-23 (23). As psoriasis severity (measured as Psoriasis Area Severity Index, such, CLA+ memory T cells should be considered an important PASI) in patients. Moreover, in guttate psoriasis, the peak in IL-9 source of IL-17F in psoriasis. Because IL-17A and IL-17F production was found on patients having the highest ASO levels homodimers and heterodimer share their signaling receptor, indicating higher exposure to S. pyogenes. constituted by the IL-17RA and IL-17RC subunits, they induce similar gene expression patterns. Nonetheless, the relevance of GUTTATE PSORIASIS: WHERE GENETIC IL-17F in psoriasis pathogenesis has been shown in patients AND ENVIRONMENTAL FACTORS and animal models. For example, IL-17F knock-out (KO) mice are more resistant to imiquimod-induced psoriasiform INTERACT PRODUCING TH17 RESPONSE inflammation than the IL-17A KO counterparts (31). In humans, BY CLA+ T CELLS the rapid clinical efficacy achieved by brodalumab, a monoclonal antibody targeting the IL-17RA subunit (that is part of the Guttate psoriasis is a form of psoriasis that is strongly associated receptor for IL-17A, IL-17F, IL-17A/F heterodimer, and IL-25) with the genetic predisposing allele HLA-Cw6 and is commonly first showed the advantages of targeting beyond IL-17A (32, 33). triggered by Streptococcus pyogenes throat infections (37). This Most importantly, the promising results of the phase 2 and phase situation has provided a good opportunity to study genetic 3 clinical trials studying the nanobody sonelokimab and the and environmental factors influence on cytokine production by monoclonal antibody (mAb) bimekizumab, respectively, both of CLA+ T cells in psoriasis (28). The coculture of CLA+ T cells which target IL-17A, IL-17F, and IL-17A/F, further highlight the activated with S. pyogenes clearly demonstrated that non-treated clinical relevance of IL-17F in psoriasis patients (34, 35). guttate psoriasis patients produced significantly more IL-17A/F cytokines than IFN-γ. However, the most interesting finding was that guttate psoriasis patients carrying the HLA-Cw6 allele and/or whose flare was produced by S. pyogenes pharyngitis, IL-9 IS NOT PRODUCED TRANSIENTLY BY in comparison to guttate psoriasis patients that did not fulfill those criteria, significantly produced more IL-17A/F by CLA+ CLA+ T CELLS IN HUMAN PSORIASIS T cells. Similar dominant IL-17 response also induced genes In humans, IL-9-secreting CD4+ T cells, namely Th9, have been that belong to the IL-17 transcriptome in keratinocytes such as described as a distinct T cell population with preferential skin DEFB4, LCN2, IL-8, but no to the IFN-γ (CXCL9, CXCL10, and tropism (36). In this work, CLA+ Th9 cells were transiently CXCL11). Such influence of genetic and microbe infection on induced by Candida albicans-pulsed monocytes particularly but IL-17 response in guttate psoriasis patients has been clarified by also after non-physiological polyclonal activation, supporting the analyzing CLA+ T cells. association of Th9 cells to the skin regardless of their antigen specificity and using lymphocytes from healthy subjects. This PLAQUE PSORIASIS: IL-17 PRODUCTION transitory Th9 induction peaked just before the increase of IL- AND PATIENTS HETEROGENEITY 17 and IFN-γ induction, suggesting a paracrine regulation by IL-9 that was further confirmed by its own neutralization. More Chronic plaque psoriasis, or psoriasis vulgaris, is the most interestingly, a significant increase of IL-9+ cells, mostly CD3+ common form of psoriasis that is generally diagnosed based on CD4+ T cells, was found in lesional psoriatic skin compared to the shape and location of the lesions and the persistent duration atopic dermatitis and healthy cutaneous tissue. of the disease. Heterogeneity among plaque psoriasis patients However, when studying the functional role of IL-9 in has been suggested (38) but it is still not well-characterized. psoriasis patients (plaque and guttate forms) in our coculture Nowadays, plaque psoriasis is considered a single entity in most model (29), we found that, after S. pyogenes activation, the kinetic of the clinical studies yet. However, recent results have suggested of IL-9 production measured in CLA+ T cells and epidermal cells that the IL-17 cytokines responses by CLA+ T cells may be coculture supernatants was similar to those of IL-17A and IFN-γ, differentially influenced by environmental factors, particularly progressively increasing over time and dependent on MHC class by exposure to microbes that could favor IL-17 production in I and class II presentation, which contrasted with the transient chronic plaque psoriasis. IL-9 induction reported before (36). Interestingly, IL-9 partially Streptococcus pyogenes-induced IL-17 response by CLA+ T enhanced SE-induced IL-17A, but not IFN-γ, secretion by CLA+ cells in psoriasis patients is higher when patients present higher Frontiers in Medicine | www.frontiersin.org 3 October 2021 | Volume 8 | Article 731911 de Jesús-Gil et al. Cytokines and CLA+ T Cells in Psoriasis FIGURE 1 | Human CLA+ memory T cells and cytokines in psoriasis. As the subset of memory T cells associated to the cutaneous immune system, circulating CLA+ T cells are key responders to lesional pro-inflammatory cytokines and relevant microbes that induce important type 17 responses, therefore contributing to the pro-inflammatory loop leading to the appearance of psoriatic lesions. (A) IL-15 and IL-23, which are mainly produced by keratinocytes as well as epidermal and dermal dendritic cells, synergistically activate CLA+ CD4+ memory T cells from psoriasis patients leading to an increased induction of IL-17F and IL-17A cytokines, whereas IFN-γ secretion is likely mediated by CLA+ CD8+ memory T cells in psoriasis but also in healthy controls. (B) S. pyogenes and C. albicans antigens, presented by epidermal antigen presenting cells, have been proved to induce significantly higher IL-17A/F and IL-9 responses by CLA+ memory T cells in psoriasis patients, compared to CLA− T cells. Besides, S. pyogenes-induced IL-9 has shown to enhance IL-17A responses, further reinforcing the pro-inflammatory loop underlying psoriasis lesions. CLA, cutaneous leukocyte-associated antigen; KCs, keratinocytes; LCs, Langerhans cells; dDCs, dermal dendritic cells; APCs, antigen presenting cells. This figure was created using Servier Medical Art (smart) images. titer of immunoglobulin A against S. pyogenes extract (39). We potent inducer of IL-17 cytokines in humans (43). Importantly, reported that anti-SE IgA values in psoriasis patients (both immune response against this fungus is mainly mediated by plaque and guttate forms) are higher than in atopic dermatitis CLA+ memory T cells, further supporting the pro-inflammatory and healthy controls. But, most importantly, we found that loop present at cutaneous lesions in psoriasis patients (30). increased mucosal exposure to S. pyogenes was present in chronic Interestingly, non-treated chronic plaque psoriasis patients, plaque psoriasis patients despite negative ASO titer and no clear without clinical signs of candidiasis, present increased levels of association of the current flare with Streptococcal infection. This both IgA and IgG specific for C. albicans in plasma. In particular, finding is of special interest since there may be multiple cases of CLA-dependent IL-17A and IL-17F responses correlated with plaque psoriasis where the implication of Streptococcus pyogenes Candida-specific IgA, but not IgG, only in chronic plaque has been discarded, but the bacteria may still be present at the psoriasis. Additionally, a proteomic study of plasma samples tonsils and contribute to recurrent flares in those patients. In from 114 non-treated plaque psoriasis patients revealed that, this regard, a recent population-based cohort study has reported those with higher anti-Candida IgA levels presented increased how tonsillectomy diminished the risk of developing psoriasis levels of proteins involved in antimicrobial humoral response, (40). Future studies should confirm how such heterogeneity may especially proteins showing anti-candida activity [such as influence the natural history of psoriasis disease and/or how eosinophil cationic protein (ECP/RNASE3), Chitinase-3-like different patients respond to specific treatments. protein 1 (CHI3L1) or azurocidin]. These findings point out the Moreover, chronic plaque psoriasis patients also present implication of Candida albicans in chronic plaque psoriasis, a increased exposure to Candida albicans (CA) (41, 42), that is a matter that we believe should be further explored in the clinic. Frontiers in Medicine | www.frontiersin.org 4 October 2021 | Volume 8 | Article 731911 de Jesús-Gil et al. Cytokines and CLA+ T Cells in Psoriasis Altogether, these results support the existence of heterogeneity this field. In this regard, the possible role of CLA+ memory T cells among chronic plaque psoriasis patients that can influence in the development of psoriatic arthritis (PsA) was early explored IL-17 production and, thus, the evolution of the course of but discarded, due to the absence of CLA+ memory lymphocytes psoriasis disease. within synovial tissue (44, 45). The relevance of heterogeneity in chronic plaque psoriasis due to different immunoglobulins DISCUSSION specific for microorganisms and CLA+ T cells-dependent IL- 17A/F responses is particularly interesting since these cytokines, In plaque and guttate forms psoriasis, the IL-17 response derived in contrast to others that are also increased in lesions, are from CLA+ T cells is clearly influenced by different factors validated as safe and clinically effective targets by the use of that are related to patient features and that can be studied ex neutralizing monoclonal antibodies (46). vivo using circulating memory T cells belonging to the regional Nonetheless, this review presents some limitations, as other cutaneous immune system (Figure 1). Using clinical samples types of psoriasis (pustular, palmoplantar or inverse), have not from non-treated patients has allowed relating in vitro cytokine been addressed and the study of additional relevant cytokines responses with clinical data in a translational way. For example, that are present within psoriatic lesions, such as TNF-α or IL-36, these studies reported increased production of IL-17F over IL- in the context of CLA+ memory T cells remains underexplored. 17A by skin associated T lymphocytes, which is reflected in Eventually, these limitations evidence how much research is the clinic as the greatest response of bimekizumab (neutralizing still needed to completely unveil the intricate between cytokines both IL-17A/F) (34). Also, this approach has shown that guttate and the cutaneous immune system in the context of psoriasis. psoriasis patients positive for the HLA-C predisposing allele Any translational approach that helps to better characterize and/or the ASO perform increased cutaneous pro-inflammatory cytokine biology in the context of the cutaneous immune response by CLA+ T cells. In the end, how CLA+ memory T cells response will be essential to fully understand patients responses are the link between relevant disease triggers and the increased to current therapies and to continue developing novel strategies IL-17 response observed in psoriatic skin. in the future. Mouse models or complex in vitro systems, although they are key to study basic pathogenic mechanisms, do not integrate AUTHOR CONTRIBUTIONS elements that can influence IL-17 responses in patients such as the genetic background or their exposure to microbes able to CJ-G: writing and figure design. 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Microbe-Dependent induction of IL-9 by CLA+T cells in potential conflict of interest. psoriasis and relationship with IL-17A. J Invest Dermatol. (2018) 138:580– 7. doi: 10.1016/j.jid.2017.08.048 Publisher’s Note: All claims expressed in this article are solely those of the authors 30. De Jesús-Gil C, Sans-de San Nicolàs L, Ruiz-romeu E, Ferran M, Soria- and do not necessarily represent those of their affiliated organizations, or those of martínez L, García-jiménez I, et al. Interplay between humoral and CLA + the publisher, the editors and the reviewers. Any product that may be evaluated in T cell response against Candida albicans in psoriasis. Int J Mol Sci. (2021) this article, or claim that may be made by its manufacturer, is not guaranteed or 22:1–14. doi: 10.3390/ijms22041519 31. Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, et endorsed by the publisher. al. Rorγt + innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J Clin Invest. (2012) 122:2252–6. doi: 10.1172/JCI61862 Copyright © 2021 de Jesús-Gil, Sans-de San Nicolàs, García-Jiménez, Ferran, Pujol 32. Foulkes AC, Warren RB. Brodalumab in psoriasis: evidence to date and and Santamaria-Babí. This is an open-access article distributed under the terms clinical potential. Drugs Context. (2019) 8:212570. doi: 10.7573/dic.212570 of the Creative Commons Attribution License (CC BY). The use, distribution or 33. Warren RB, Hansen JB, Reich K, Paul C, Puig L. Complete clearance and reproduction in other forums is permitted, provided the original author(s) and the psoriasis area and severity index response for brodalumab and ustekinumab copyright owner(s) are credited and that the original publication in this journal in AMAGINE-2 and−3. J Eur Acad Dermatology Venereol. (2021) 35:450– is cited, in accordance with accepted academic practice. No use, distribution or 7. doi: 10.1111/jdv.16816 reproduction is permitted which does not comply with these terms. 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