MINI REVIEW published: 23 March 2021 doi: 10.3389/fimmu.2021.652613 The Translational Relevance of Human Circulating Memory Cutaneous Lymphocyte-Associated Antigen Positive T Cells in Inflammatory Skin Disorders Carmen de Jesús-Gil 1† , Lídia Sans-de SanNicolàs 1† , Irene García-Jiménez 1 , Marta Ferran 2 , Antonio Celada 3 , Anca Chiriac 4 , Ramon M. Pujol 2 and Edited by: Luis F. Santamaria-Babí 1* Daniel H. Kaplan, 1 University of Pittsburgh, United States 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 Reviewed by: Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Macrophage Biology, Julien Seneschal, Department of Cellular Biology, Physiology, and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain, Université de Bordeaux, France 4 Department of Dermatophysiology, Apollonia University, Iasi, Romania Koji Yasutomo, Tokushima University, Japan *Correspondence: Circulating memory T cells are heterogeneous in their tissue tropism. The skin-seeking Luis F. Santamaria-Babí T cell subset expresses the cutaneous lymphocyte-associated antigen (CLA) on their luis.santamaria@ub.edu surface. CLA+ memory T cells not only migrate from blood to skin but also recirculate † These authors have contributed between blood and skin. Studying CLA+ memory T cells in cutaneous diseases has equally to this work and share first authorship allowed a better understanding of immune-inflammatory mechanisms that take place. The analysis of the phenotypical features of these cells, their antigen specificity, cytokine Specialty section: production profile, and changes in relationship to clinical status and therapies among This article was submitted to T Cell Biology, other characteristics have led to the concept that they constitute peripheral cellular a section of the journal biomarkers in T cell-mediated cutaneous conditions. CLA+ memory T cells are of Frontiers in Immunology relevance in the pathogenesis of several cutaneous diseases, such as psoriasis (PSO), Received: 12 January 2021 atopic dermatitis, vitiligo, and drug-induced allergic reactions, to name a few. The Accepted: 09 February 2021 Published: 23 March 2021 interaction of circulating CLA+ T cells with skin-resident cells has been investigated in Citation: different ex vivo coculture models made out of clinical samples. Interestingly, microbes de Jesús-Gil C, Sans-de that are present in the skin or related with human skin diseases are preferentially SanNicolàs L, García-Jiménez I, Ferran M, Celada A, Chiriac A, recognized by CLA+ T cells. Thus, the interaction of Streptococcus pyogenes with Pujol RM and Santamaria-Babí LF CLA+ T cells in PSO is providing novel concepts that help to understand disease (2021) The Translational Relevance of immunopathogenesis. The goal of this review is to present latest results in the field Human Circulating Memory Cutaneous Lymphocyte-Associated of CLA+ T cells in T cell-mediated inflammatory skin diseases and their translational Antigen Positive T Cells in relevance for human immunodermatology. Inflammatory Skin Disorders. Front. Immunol. 12:652613. Keywords: skin-homing lymphocytes, cutaneous inflammation, CLA+ T cell, human, translational, doi: 10.3389/fimmu.2021.652613 immunodermatology Frontiers in Immunology | www.frontiersin.org 1 March 2021 | Volume 12 | Article 652613 de Jesús-Gil et al. CLA+ T Cells in Cutaneous Diseases INTRODUCTION (S. pyogenes) infection is the best characterized clinically relevant trigger of PSO in patients (13). The molecular mechanism that The existence of a cutaneous immune system in humans was links S. pyogenes and IL-17 response is starting to be clarified postulated almost 50 years ago (1) and recently reformulated in PSO (14). Only CLA+ memory T cells, but not CLA− , (2). In order to understand the adaptive immune response preferentially respond to S. pyogenes in an autologous coculture regionally, for those human memory T cells that belong to of T cells and cutaneous epidermal cells from patients with the cutaneous immunity, a skin-specific cell marker would be PSO (15). Besides, patients with PSO who are negative for of great help. The cutaneous lymphocyte-associated antigen antistreptolysin O (ASO) antibody present increases levels of (CLA) constitutes a relevant marker that identifies the subset of immunoglobulin (Ig) A, but not IgG, to S. pyogenes, which are memory T lymphocytes functionally related to skin physiology. directly associated with CLA+ T–cell-dependent IL-17 response CLA was discovered in 1990 by serendipity as a cell surface to S. pyogenes in vitro (16). These results suggest that increased carbohydrate preferentially expressed by T cells present in exposure to S. pyogenes, as demonstrated by the presence of cutaneous inflamed tissues, but no other organs (3). Since then, specific humoral immune response even in patients with ASO a comprehensive number of scientific evidence described in negative, upon recognition by CLA+ T cells can fuel pathogenic humans support the role of CLA as a relevant marker to identify IL-17 production. Remarkably, similar association has been skin-associated memory T cells involved in T cell-mediated recently described for Candida albicans, which is a potent cutaneous inflammation, that provide translational information IL-23/Th17 inducer too (17). Some other new mechanisms in numerous different human skin diseases. CLA is more than in PSO relating CLA+ T cells and IL-17 have been recently a mere cell surface carbohydrate (3), preferentially expressed on revealed. The cytokine milieu present in psoriatic lesions can CD45RO+ T cells, which binds to endothelial E-selectin and influence IL-17 response by CLA+ T cells. IL-15 and IL-23, both mediates cell adhesion and transendothelial migration together present in psoriatic lesions, have been shown to synergize with with other molecules such as lymphocyte function-associated CLA+ T cells and autologous epidermal cells to produce IL- antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), and 17A and IL-17F in PSO. This phenomenon occurs without the C–C chemokine receptor type 10 (CCR10) (4). CLA+ T use of any exogenous stimulus, in a major histocompatibility lymphocytes are found in circulation and in inflamed and healthy complex (MHC)-dependent way, and independently of resident skin but not infiltrating other non-cutaneous sites (3, 5). The T cells (18), but it does not take place using CLA− T cells fact that some CLA+ T cells are found in circulation deserves or cells from healthy controls. This is an example of how special attention due to the consequences of blocking LFA-1 in psoriatic skin cytokine microenvironment interacts specifically patients with atopic dermatitis (AD) and psoriasis (PSO) (6, 7). with skin-related memory T cells generating the IL-17 response During treatment with efalizumab, patients present a circulating critical for PSO initiation and maintenance. IL-9 is another lymphocytosis of CLA+ T cells. If the treatment is interrupted, a cytokine studied in the context of CLA+ T cells function in flare in disease occurs. One explanation to this effect is that CLA+ PSO in the ex vivo coculture model with autologous epidermal T cells recirculate between blood and skin during cutaneous cells (19). Streptococcus pyogenes preferentially triggers IL-9 in inflammation. Blocking their extravasation through LFA-1 leads CLA+ T cells together with other mediators such IL-17A. In to accumulation of those cells in blood, consequently when the contrast to the previous studies where IL-9 is not induced by blockade is released the cells enter abruptly into lesions and natural stimulus, IL-9 is produced in a time-dependent way and make flare. This mechanism of CLA+ T cell recirculation has not transiently. Interestingly, the neutralization of S. pyogenes- important implications for the translational relevance of studying induced IL-9 by CLA+ T cells decreased IL-17A production circulating CLA+ T cells in human inflammatory skin disorders by 50%. (Figure 1A). CLA+ memory T cells participate in pathological Furthermore, the descriptive analysis of T cell subpopulations mechanisms of inflammatory disorders by recognizing key in patients with PSO revealed differential role for CD4+ and triggers of disease and producing cytokines that affect cells CD8+ T lymphocytes, whereas CLA expression is associated of the skin. The phenotype of those cells can reflect clinical with skin recruitment of CD4+ central memory T cells (TCM ), status of the patients. The goal of this review is to update this particularly those CCR4+ and CCR6+ , suggesting a specific role information on circulating CLA+ T cells in different human skin for these cells in patrolling the skin compartment; CD8+ T inflammatory diseases. cells are more likely to accumulate in psoriatic skin and stay as resident memory T cells (TRM ) (20). Still, there is a need for PSORIASIS psoriatic models, closely representing human disease, to be used as drug screening platforms. Recently, Shin et al. (21) developed In PSO, CLA+ T cells are contributing to understand the psoriatic human 3D skin constructs (pHSCs) by incorporating pathological mechanisms from a translational point of view using T cells, over the classical approach based on the use of patient- ex vivo studies with clinical samples. Although PSO is considered derived keratinocytes or fibroblasts treated with PSO-related to be triggered by cathelicidin (LL-37) (8) and interferon (IFN)- cytokines. As lymphocyte source, they tested in vitro polarized alpha (9, 10), the translation of this mechanism into patients Th1/Th17 cells and CCR6+ CLA+ T cells from the patients with is complex since anti-IFN-alpha (11), anti-IFN-gamma (12), PSO, both of which showed psoriatic phenotype on epidermal and anti-IL-22 do not induce clinical improvement, to name cells along with disease-associated cytokine profile. Interestingly, a few clinically invalidated mechanisms. Streptococcus pyogenes when different psoriatic drugs were tested, those pHSCs with Frontiers in Immunology | www.frontiersin.org 2 March 2021 | Volume 12 | Article 652613 de Jesús-Gil et al. CLA+ T Cells in Cutaneous Diseases FIGURE 1 | Translational relevance of human circulating memory CLA+ T cells in inflammatory skin disorders. (A) In skin-draining lymph nodes, antigen-specific Langerhans cells encounter naïve T cells generating memory T cells that express the skin-homing receptor CLA. CLA+ memory T cells enter the general circulation, through efferent lymphatic vessels, and will extravase to inflamed skin. Some CLA+ memory T cells leave cutaneous tissue through afferent lymphatic vessels, (Continued) Frontiers in Immunology | www.frontiersin.org 3 March 2021 | Volume 12 | Article 652613 de Jesús-Gil et al. CLA+ T Cells in Cutaneous Diseases FIGURE 1 | Recirculating back to the bloodstream, whereas, others are retained at the epidermal layer as resident memory T cells. (B) Principal antigen/allergen/autoantigen-induced effector functions of CLA+ memory T cells in human inflammatory cutaneous conditions. AA, alopecia areata; ACD, allergic contact dermatitis; AD, atopic dermatitis; CLA, cutaneous-associated lymphoid antigen; CLP, cutaneous lichen planus; DRESS, drug rash with eosinophilia and systemic symptoms; LC, Langerhans cells; OLP, oral lichen planus; PSO, psoriasis; TRM , T-resident memory. This figure was created using images from Smart Servier (https://creativecommons.org/licenses/by/3.0/), WikiHow (https://creativecommons.org/licenses/by-nc-sa/3.0/) and Freepik.es (@brgf). CCR6+ CLA+ T cells responded differently to the ones with subsets in patients with AD compared to HC and patients with in vitro polarized Th1/Th17 cells, highlighting the relevance of PSO, predominantly in the skin-homing subset, and correlates using patient-CLA+ T cells to better address and even anticipate with SCORAD. In contrast, the expression of human leukocyte specific therapeutical responses in vitro, moving one step forward antigen (HLA)-DR, the chronic T cell activation MHC class II to personalized medicine in PSO field. antigen, is similar in infants regardless AD status, but increases The CLA+ lymphocytes have been extensively studied in with age reaching high levels in adult patients with AD vs. the context of PSO disease, as last reviewed here (22). The HC and patients with PSO, particularly among CLA+ T cell importance of CLA+ T cells in PSO resides not only in their population, which correlates with SCORAD (28, 29, 31). Besides, contribution to lesion formation but also in their role as frequencies of CLA+ regulatory T cells (Tregs ) are higher in AD peripheral biomarkers of successful treatment, as it has been compared with HC and patients with PSO, and they correlate confirmed by recent studies. For example, a significant reduction with both ICOS and HLA-DR, and also with clinical parameters of circulating CLA+ T cell, as well as IL-6 and IL-22, has (SCORAD and IgE levels) (31). Intriguingly, OX40, another been associated with clinical efficacy after anti-tumor necrosis costimulatory molecule predominantly expressed on T cells and factor (TNF)-alpha treatment (23). Similarly, a reduction on required for long-term memory responses, is mainly expressed the number of CLA+ Th17/Tc17 and Th22/Tc22 cells was by CLA+ memory T cells in both patients with AD and HC observed after 6 weeks of phototherapy and balneotherapy, which (32). A recent epigenetic report has extended the knowledge positively correlated with the reduction on PSO area and severity on the CLA+ T cells of male adult patients with severe AD index (PASI) score (24). and allergen-specific IgE sensitization (33). Peripheral blood mononuclear cells sorted into four different T cell populations (CD8+ , CD4+ , CD4+ CD45RA+ , and CD4+ CLA+ ) have ATOPIC DERMATITIS revealed differentially DNA methylations in 40 protein-coding The CLA+ T cells are involved in initiation and perpetuation genes in the CD4+ CLA+ subset in patients with AD vs. HC. of AD (25), as they are functionally related to cutaneous Among them, IL-13 gene promoter shows decreased methylation inflammation (4, 26). Recent blood phenotyping studies on levels, which negatively correlate with IL13 mRNA expression peripheral blood mononuclear cells from patients with AD and levels in this subset. healthy controls (HC) have illustrated increased percentage of CLA+ memory T cells in moderate-to-severe patients with AD VITILIGO compared with age-matched HC, but a decrease with increasing age only in patients with AD (27, 28). The expansion of CLA+ Melanocyte-specific circulating memory CD8+ CLA+ T cells T cells is accompanied by predominance of CLA+ Th2/Tc2 and induce melanocyte apoptosis, together with other mechanisms, Th22/Tc22 response in AD. Although CLA+ Th2 cell counts are such as cell detachment triggered by E-cadherin disruption similarly increased across all ages and are significantly higher (34), contribute to melanocyte loss and the development of than HC, CLA+ Th22 cell counts increase with age only in depigmented skin lesions in vitiligo. Several blood endotyping AD and its levels are also higher than that in HC (27–29). studies have depicted that patients with vitiligo have low CLA+ Th22 levels correlate with severity parameters [scoring frequencies of circulating CD4+ /CD8+ CLA+ TEM /TCM cells atopic dermatitis (SCORAD) and eczema area and severity compared to patients with PSO, being similar to HC, supporting index], pruritus, and IL-17-producing cells (29, 30). CLA+ IL- that CLA+ T cells migrate to the skin (35, 36). Within T cell 13+ T cells positively correlate with SCORAD, serum IgE levels, subsets, patients with vitiligo have the highest frequency of and IL-22 frequencies (27). Regarding Th1/Tc1 cell subsets, CD4+ /CD8+ CLA+ T cells producing IFN-gamma compared AD is characterized by decreased CLA+ Th1/Tc1 frequencies with patients with AD, PSO, and alopecia areata (AA), and HC in conjunction with negative correlations between CLA+ IFN- (35), supporting that vitiligo is caused by a type 1 T cell response gamma+ T cells and SCORAD, and CLA+ IL-13+ and IL-22+ (37, 38). Consistent with the literature describing CD8+ T cell populations. CLA+ Th1 frequencies increase with age both in AD role in melanocytes death under IFN-gamma stimulation, CD8+ and HC, but do not reach the HC levels, and they are associated CLA+ T cell population producing IFN-gamma predominates with disease duration. All these data support an imbalanced over CD4+ CLA+ T cell subset in patients with vitiligo (35). CLA+ Th1:Th2 cell ratio that increases with age both in AD and Interestingly, the same study showed the highest frequency of HC, but remains decreased in AD (27–29). CD4+ /CD8+ CLA+ T cells producing IL-9 in patients with The expression of the indicator of T cell mid activation, vitiligo in comparison with patients with AD, PSO, and AA inducible costimulatory molecule (ICOS), has been reported and HC, pointing out for the first time a possible role for IL- to be enhanced both in CLA+ and CLA− memory T cell 9 on the physiopathology of vitiligo. Furthermore, Th17 subset, Frontiers in Immunology | www.frontiersin.org 4 March 2021 | Volume 12 | Article 652613 de Jesús-Gil et al. CLA+ T Cells in Cutaneous Diseases either CLA+ or CLA− , was also increased in vitiligo compared Although the role of CLA+ T cells in non-immediate drug- to patients with HC, AD and, surprisingly, with PSO, a disease induced cutaneous reactions was first reported two decades ago associated to be driven by IL-17 activation. Regarding CLA+ (46), there is still a lot to learn about them in drug allergy. Th22 subset, it was also augmented in patients with vitiligo Recently, it has been shown that in drug rash with eosinophilia compared to patients with PSO and HC (35). In accordance and systemic symptoms (DRESS) (47), IL-4 and IL-13 producing to this fact, IL-22 has been reported to participate in the CD4+ T cells are increased during active disease and decline pathogenesis of vitiligo, as it promotes IL-1β secretion from with recovery, pointing at the relevance of CLA+ Th2 cells in keratinocytes what cause the suppression of melanogenesis and the pathogenesis of DRESS. In β-lactam hypersensitivity, a new melanocyte migration as well as the induction of melanocyte T cell subset has been proposed, in which blood- and skin- apoptosis (39). The active participation of autoreactive CD8+ derived clones specific for piperacillin expressed high levels of T cells in vitiligo indicates that immune tolerance has been skin-homing chemokine receptors and migrated in the presence disrupted. Several studies have shown that patients with vitiligo of the ligands CCL27 (48). have a reduced amount of infiltrating Tregs in non-lesional, perilesional, and lesional skin (40, 41). Patients with vitiligo also have fewer amounts of total circulating Tregs compared to DISCUSSION patients with AD and PSO, the difference being not that obvious The involvement of CLA+ T cells in different inflammatory skin in the CLA+ Tregs subset (35). disorders, with diverse pathological immunological mechanisms, makes them interesting for human dermatology (Figure 1B). ALOPECIA AREATA Also, circulating memory CLA+ T cells specific for disease relevant antigens/allergens have reported, for example, S. The CLA relevance in AA in humans was first revealed by pyogenes in PSO (22) or house dust mite and Staphylococcus Yano et al. (42), describing higher positivity in peripheral blood aureus enterotoxin B in AD (4). Despite the functional relevance mononuclear cells, CD4+ and CD8+ lymphocytes from AA of memory CLA+ T cells has been better described in PSO and compared with HC, and that CLA positivity negatively correlated AD (4, 22, 49); their potential role in other T cell-mediated skin with clinical improvement. Later, phenotyping research on conditions is still to be fully investigated. Various approaches peripheral blood mononuclear cells described that CLA+/− Th2- that involve minimal manipulation of those cells are providing cell frequencies are similar between patients with AA and AD, immunological information that relates to clinic in a translational both higher than HC, and they correlate with AA severity; way. Although animal models and complex in vitro models however, skin-homing Tc2 and Th22 are significantly higher are providing important information to understand human in AA vs. HC (43). Also, the positive correlations have been inflammatory skin disorders, there is a need to use clinical human reported not only between CLA+ Th2/Tc2 and Th22/Tc22 but samples to gather genetic background and real diseased skin also between CLA+ Th17/Tc17 and Th22/Tc22, particularly in cells of patients (50). For example, animal models cannot reflect the CD8+ subset. In addition to this, skin-homing CD4+ /CD8+ the immune response present in patients after several years of TCM -cell counts are higher in patients with AA, compared with chronic cutaneous inflammation and numerous flares. Different HC and patients with AD, unlike CD4+ /CD8+ TEM frequencies, aspects can influence the immune response in inflammatory skin and CD4+ , but not CD8+ , subset shows HLA-DR activation diseases such as genetic background, disease endotype/patient in TCM cells. Regarding Tregs cells, diminished frequencies of heterogeneity, local antigen presentation by human epidermal total and CLA+ Tregs have been described in patients with AA cells, impact of environmental triggers of disease, or neurogenic compared to HC and patients with AD, which correlate with inflammation. This integrated view is the approach that CLA+ T skin-homing Th9, Th2/Tc2, Tc17, and Tc22 counts. cells exploration follows. Nonetheless, the interplay between circulating and tissue- OTHER INFLAMMATORY SKIN DISEASES resident CLA+ T cells should be further addressed. Particularly since the latter have been described to persist in resolved skin In lichen planus, there is an accumulation of CLA+ T cells in after treatment and to be involved in the recurrence of cutaneous the epithelium of the buccal mucosa in oral lichen planus (OLP), lesions in PSO, vitiligo, or fixed drug eruptions (51). and in the epidermis of skin biopsies in cutaneous lichen planus We are clearly still at the top of the iceberg unraveling the (CLP) (44). Increased E-selectin expression in lesional biopsies information that those lymphocytes can provide for human from OLP over perilesional tissue, together with a significantly inflammatory cutaneous conditions. For all these translational higher proportion of CD8+ CLA+ T cells were observed by capacities, circulating memory CLA+ T cells can be proposed the immunohistochemical analysis. It has been shown cutaneous as peripheral cellular biomarkers in human inflammatory T cell-attracting chemokine (CTACK, also CCL27) secretion skin disorders. by oral keratinocytes, which increased in the presence of IFN- gamma and actively attracted CLA+ memory T cells to the oral epithelium. Although both normal oral mucosa and lesions AUTHOR CONTRIBUTIONS from chronic OLP showed low levels of CTACK expression, it may still play a role in early recruitment of T cells and CJ-G and LS: equal contribution writing and experimental. LS-B: immunopathogenesis of OLP (45). principal investigator, director, founding, and corresponding Frontiers in Immunology | www.frontiersin.org 5 March 2021 | Volume 12 | Article 652613 de Jesús-Gil et al. CLA+ T Cells in Cutaneous Diseases author. RP: clinical, translational work, and founding. ACh: Carlos III; PI09/2222, PI13/01845, and PI13/01716) and clinical and translational work. ACe: immunology expertise. FIS/ISCIII 2016 (PI16/01573 and PI016/00532).This work MF: clinical and translational work. IG-J: contribution writing. was supported by European Regional Development Fund All authors contributed to the article and approved the grants. E. R. R. was granted a PhD fellowship from submitted version. the Ministerio de Educación, Cultura y Deporte of the Spanish Government (FPU13/02308). CJ-G was granted FUNDING by a PhD fellowship from the Agency for Management of University and Research Grants of the Generalitat de This study was funded by FIS/ISCIII 2013 (Ministerio Catalunya (FI-2018), co-financed with European Social de Economía y Competitividad e Instituto de Salud Found FEDER. REFERENCES in patients with guttate psoriasis. J Allergy Clin Immunol. (2016) 138:491– 9.e6. doi: 10.1016/j.jaci.2016.02.008 1. Streilen JW. Lumphocyte traffic, T-cell malignancies and the skin. J Invest 16. de Jesús-Gil C, Sans-de San Nicolás L, Ruiz-Romeu E, Ferran M, Soria- Dermatol. 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The use, Mol Med. (2018) 22:4335–43. doi: 10.1111/jcmm.13723 distribution or reproduction in other forums is permitted, provided the original 41. Klarquist J, Denman CJ, Hernandez C, Wainwright DJ, Strickland FM, author(s) and the copyright owner(s) are credited and that the original publication Overbeck A, et al. Reduced skin homing by functional Treg in vitiligo. Pigment in this journal is cited, in accordance with accepted academic practice. No use, Cell Melanoma Res. (2010) 23:276–86. doi: 10.1111/j.1755-148X.2010.00688.x distribution or reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 7 March 2021 | Volume 12 | Article 652613