Circulating CLA⁺ Memory T Cells in Skin Diseases: A Translational Perspective

Abstract

Circulating cutaneous lymphocyte-associated antigen–positive T cells constitute a subset of memory T cells with a unique phenotype, effector function, and therapeutic relevance because they reflect the regional functions of the cutaneous immune system. These cells are involved in the pathological mechanisms of diverse cutaneous diseases. This review brings updated translational insights into these cells and identifies key questions for future research in the field.

Introduction

The cutaneous lymphocyte-associated antigen (CLA) marks a subset of effector memory T cells with a specific affinity for the skin, enabling their recirculation between the skin and blood during cutaneous inflammation and reflecting immune abnormalities in the skin (Nicolàs et al, 2024). CLA is a carbohydrate modification of PSGL-1 that interacts with endothelial and platelet selectins (E-selectin and P-selectin) on postcapillary venules in the skin and, together with other adhesion molecules and chemokine receptors, mediate the extravasation of CLA⁺ T cells at cutaneous sites (Fuhlbrigge et al, 1997). Its expression is induced on CD45RO⁺ memory T cells within skin-draining lymph nodes and is found on over 90% of skin-infiltrating T cells, compared with less than 20% of T cells in other peripheral tissues (Picker et al, 1993). Approximately 15% of circulating T cells also express CLA. Recently, new translational research in the field of circulating CLA⁺ memory T cells in dermatology has demonstrated the interest of this singular lymphocyte subset in understanding T-cell–mediated human skin diseases.

LFA-1, an integrin expressed on CLA⁺ T cells, mediates their translocation into inflamed skin by binding to ICAM-1 on endothelial cells, together with VLA-4/VCAM-1 and E-selectin with CLA (Santamaria Babi et al, 1995). This interaction facilitates the movement of these memory T cells from the bloodstream, a process that is crucial for the recruitment of immune cells to sites of cutaneous inflammation (Santamaria Babi et al, 1995). The significance of the LFA-1/ICAM-1 interaction has been highlighted in clinical studies utilizing efalizumab, an anti–LFA-1 mAb designed to inhibit this binding (Takiguchi et al, 2007). Although efalizumab successfully reduced the infiltration of CLA⁺ memory T cells into the skin and temporarily improved clinical symptoms of atopic dermatitis (AD) (Takiguchi et al, 2007), it conversely resulted in a fourfold increase in circulating CLA⁺ effector memory T cells in the blood (Harper et al, 2008). This phenomenon illustrates “reverse” migration from skin to blood through the lymphatic system (Yawalkar et al, 2000). After the cessation of treatment, these cells exhibited a tendency to migrate swiftly back into the skin, leading to clinical rebound and disease exacerbation (Takiguchi et al, 2007). This rebound effect has also been documented in other inflammatory skin conditions, such as psoriasis, indicating a broader implication of this treatment mechanism across other skin diseases (Leonardi, 2004). Thus, the relevance of circulating CLA⁺ T cells may extend beyond their ability to migrate selectively into the skin because their capacity for “dehoming" and re-entering circulation suggests that they may effectively reflect cutaneous immune responses (de Jesús-Gil et al, 2021b). Besides adhesion molecules, some chemokines and their respective chemokine receptors are involved in the migration of CLA⁺ memory T cells to the skin. The skin-associated chemokine CCL27 (CTACK) is preferentially expressed in keratinocytes and preferentially binds CCR10 expressed on CLA⁺ memory T cells, mediating their migration to the skin (Homey et al, 2002). In addition, the CCR4 receptor present in CLA⁺ memory T cells (Campbell et al, 1999) also facilitates their migration to the skin (Biedermann et al, 2002).

Expression of CLA on cells beyond memory T cells

The CLA antigen is not only expressed on memory T cells. As shown in Table 1, different cell type subsets also express CLA, including memory B cells, neutrophils, and innate lymphoid cells (ILCs). The functional relevance of these CLA⁺ subsets within the context of cutaneous immune response has yet to be characterized. In addition, their clinical characterization and implications remain to be elucidated. Thus, CLA⁺ memory T cells remain the best characterized population of all CLA⁺ expressing cells. A recent publication on Dengue virus infection reported that during the acute phase of secondary natural Dengue virus infection, plasma cells and plasmablasts, unlike in healthy controls, expressed CLA and exhibited the highest clonal expansion than other B-cell subsets. These clonally expanded cells also expressed the highest levels of tissue-homing genes. In contrast, naïve and memory B cells from the same patients did not express CLA (Arora et al, 2024).

Table 1.

Cells Expressing CLA

Cell Type	Reference
Memory CD4+ T cells	Picker et al (1990)
Memory CD8+ T cells	Picker et al (1990)
ILC2	Salimi et al (2013)
ILC3	Teunissen et al (2014)
NK cells	Tsuchiyama et al (2002)
NKG2D+ CD8+ T cells	Jacquemin et al (2020)
Vγ9Vδ2 T cells	Laggner et al (2011)
Tregs	Hirahara et al (2006)
Memory B cells	Yoshino et al (1999)
Monocytes	Picker et al (1990)
Dendritic cells	Kieffer et al (2001)
Langerhans cells (CD1a+)	Yasaka et al (1996)
Neutrophils	Kieffer et al (2001)
Cutaneous T-cell Lymphoma	Picker et al (1990)

Abbreviations: CLA, cutaneous lymphocyte-associated antigen; ILC, innate lymphoid cell; Treg, regulatory T cell.

CLA expression in circulating, resident, and ex-resident memory T cells

Skin-homing CLA⁺ memory T cells, cutaneous T resident memory (TRM) cells CD69⁺CD103⁺, and circulating ex-TRM cells CD69⁻CD103⁺ are closely related, as shown in Figure 1. They share a blood–skin recirculation pathway in humans and express CLA. Recent studies have shown that reactivated TRM cells are found in circulation and are capable of migrating to tissues in chronic inflammation (Fonseca et al, 2020; Samat et al, 2021). Although these circulating ex-TRM cells retain epigenetic elements imprinted during their tissue residency, they downregulate CD69 (Buggert et al, 2018). This is the case of CD4⁺CD69⁺CD103⁺CLA⁺ TRM cells that exit the tissue and are identified in circulation as a lymphocyte subset producing IL-22 and IL-13, with the ability to home back to the skin in healthy individuals (Klicznik et al, 2019).

Figure 1.

Circulating skin-homing CLA⁺ memory T cells, cutaneous TRM cells, and peripheral ex-TRM cells are closely related in cutaneous immune responses. CLA expression identifies different T lymphocyte subsets involved in the cutaneous immune response. Skin-homing T cells migrate and seed the epidermis with TRM CD103⁺CD69⁺ cells, which are not static, as has recently been demonstrated in humans. Ex-TRM cells leave the skin, and along with dehoming processes, they return to the periphery, through efferent lymphatics and the thoracic duct. These antigen-experienced memory T cells reflect cutaneous abnormalities present in the skin and serve as cellular biomarkers. CLA, cutaneous lymphocyte-associated antigen; TRM, T resident memory.

In the blood of patients with active graft-versus-host disease, skin-derived CD4⁺ CLA⁺ ex-TRM cells are stably maintained (Strobl et al, 2021). In patients with melanoma, sequencing of paired skin and blood samples has demonstrated a clonal overlap between epidermal CD8⁺CD103⁺CD49a⁺ cells and circulating memory CD8⁺CD45RA⁻CD62L⁺ T cells, a reservoir of circulating cells with cytotoxic TRM potential (Zitti et al, 2023). Interestingly, in patients who survived metastatic melanoma and exhibited exceptional responses to immunotherapy, paired TCR sequencing identified clonotypes of memory CD8⁺ T cells within tumors that coexisted as TRM cells in the skin and as effector memory T cells in the blood (Han et al, 2021). Finally, a subset of circulating CLA⁺CD8⁺CCR10⁺ T cells, which expressed a transcriptional signature of TRM cells, including CD103, was identified in psoriatic arthritis but not in psoriasis (Leijten et al, 2021).

These initial studies support the concept that skin TRM lymphocytes are not static but instead recirculate between the skin and blood, sharing the CLA surface marker. Interestingly, circulating CD4⁺ CLA⁺ T cells exhibit phenotypic markers reflective of their tissue-resident counterparts (Czarnowicki et al, 2017). Research has shown that these circulating cells share clonotypes and functional characteristics with skin-infiltrating CLA⁺ T cells, further supporting their potential reliability as a surrogate marker for cutaneous inflammation (Czarnowicki et al, 2017; Klicznik et al, 2019). However, our understanding of their heterogeneity and functional capabilities in chronic inflammatory diseases remains limited.

Role of CLA⁺ T memory cells in AD immune dysregulation

Central to the pathogenesis of AD are T helper (Th)2–mediated immune dysregulation (eg, IL-13, IL-4, IL-31), Th22 activation, and elevated IL-17 and IFN-γ signatures in chronic lesions, alongside epidermal barrier dysfunction, cutaneous dysbiosis, and predominant infiltration of CD3⁺ CD4⁺ CD45RO⁺ CLA⁺ T cells in lesional skin (Acevedo et al, 2020; Bilsborough et al, 2006; Gittler et al, 2012; Santamaria-Babí, 2022a; Weidinger et al, 2018). Circulating T cells expressing the CLA constitute a memory T-cell subset reflecting cutaneous immunological abnormalities (de Jesús-Gil et al, 2021b).

Research has demonstrated that skin-homing memory/effector T cells play an important role in various aspects of AD, including clinical manifestations, treatment response, and potential disease biomarkers (Nicolàs et al, 2024). CLA⁺ memory T cells contribute to the initiation and perpetuation of the inflammatory landscape of AD (Ferran and Santamaria-Babi, 2010; Weidinger et al, 2018). Circulating CD4⁺ and CD8⁺ CLA⁺ T cells in patients with AD exhibit heightened expression of activation markers, including CD25, CD40 ligand, HLA-DR, and ICOS (inducible T-cell costimulator) (Akdis et al, 1997; Czarnowicki et al, 2017, 2015c). The activation marker ICOS, particularly important for Th2 activation (Tesciuba et al, 2008), is also significantly elevated in both CLA⁺ and CLA⁻ memory T cells in AD and positively correlated with disease severity (Czarnowicki et al, 2020, 2015c). Moreover, HLA-DR chronic activation in skin-homing T cells is significantly elevated in adults with AD compared with that in those with psoriasis or healthy controls (Czarnowicki et al, 2015c).

Circulating CD4⁺ and CD8⁺ CLA⁺ T cells express key type 2 cytokines, including IL-4, IL-5, and IL-13, as well as other cytokines such as IL-9, IL-17A, IL-21, IL-22, and IL-31 (Czarnowicki et al, 2021, 2015a, 2015b). More specifically, patients with AD show increased frequencies of CLA expression and selective CLA⁺ Th2/Tc2 and Th22/Tc22 expansion, accompanied by selective CLA⁺ Th1/Tc1 reduction in the blood (Czarnowicki et al, 2015b). A blood phenotyping study comparing adults and children with AD revealed that in young children aged <5 years, there is a predominance of CLA⁺ Th2 cells with reduced CLA⁺ Th1 cells, whereas other immune alterations develop over time with disease progression and chronicity (Czarnowicki et al, 2015a).

CD4⁺ and CD8⁺ CLA⁺ T cells contribute to Th2 immune response through IgE production and prevention of spontaneous eosinophil apoptosis, primarily facilitated by IL-13 and IL-5, respectively (Akdis et al, 1999, 1997). Frequencies of IL-13–producing CLA⁺ T cells as well as circulating CLA⁺ effector memory and central memory cells showed significant correlations with disease severity and serum IgE levels in patients with AD, highlighting how CLA⁺ frequencies may reflect various aspects of the disease. IL-13 contributes to the recruitment of pathogenic skin-homing T cells in AD by upregulating CCL17 and CCL22 expression on keratinocytes (Vestergaard et al, 2000).

Once at the skin, CLA⁺ T cells form dermal infiltrates and produce IFN-γ through an IL-12–dependent process, which protects them from activation-induced cell death and contributes to keratinocyte apoptosis and the subsequent development of eczema (Müller et al, 1994; Rebane et al, 2012). CD45RO⁺ CLA⁺ T cells are also a major cellular source of IL-31, a neuroimmune cytokine implicated in pruritus, inflammation, fibrosis, and epidermal barrier dysfunction in AD (Ferretti et al, 2017). The Th2 immune response can be considered as an evolutionary mechanism designed to eliminate ectoparasites and remove environmental stimuli from the host. Itching may serve as a behavioral extension of this response by promoting scratching (Yang and Zheng, 2020). Understanding how allergen-induced IL-31 relates to pruritus can be an innovative approach to studying itch in AD. Interestingly, it has been shown that house dust mite (HDM)–induced IL-31 in circulating CLA⁺ T cells correlates with patients’ pruritus and allows stratifying patients on the basis of IgE sensitization (Sans-de San Nicolàs et al, 2023). The relationship between the peripheral response to HDM, pruritus, and events occurring in skin in the context of CLA⁺ T cells response may not be coincidental because the same TCR rearrangement is found in both peripheral and lesional CLA⁺ T cells in response to HDM (Roesner et al, 2022). Although the Th2 pathway is key, other inflammatory cells also produce IL-31. These include ILC2, basophils, eosinophils, dendritic cells, macrophages, and mast cells (Clowry et al, 2024; De Jesús-Gil et al, 2020; Diluvio et al, 2006; Lilja et al, 1999; Pakkanen et al, 2010; Santamaria-Babí, 2022a). The clinical translation of these findings remains an area of ongoing research (Nicolàs et al, 2024).

IL-9 is a cytokine that is poorly characterized in AD but known to contribute to the allergic response. It has been previously described as transiently and primarily produced by CD4⁺ CLA⁺ memory T cells. A recent study has shown that HDM and staphylococcal enterotoxin B (SEB) trigger heterogeneous IL-9 production by CLA⁺ and CLA⁻ T cells in patients with AD and that allergen sensitization status reflects the varied IL-9 responses (García-Jiménez et al, 2024).

Increased levels of CCL18, a chemokine expressed by dendritic cells and other antigen-presenting cells in AD skin, has also been associated with the migration of CLA⁺ T cells to skin (Günther et al, 2005). Binding of CCL18 to CLA⁺ T cells in peripheral blood of both patients with AD and healthy controls was demonstrated to promote in vitro cellular migration in human skin–transplanted mice, highlighting further mechanisms of CLA⁺ T-cell skin homing (Günther et al, 2005).

Evidence suggests that the adaptive immune response plays a more significant role than the innate response in AD. In fact, primary data from clinical trials exploring the therapeutic potential of targeting innate immune responses, including thymic stromal lymphopoietin, IL-1α, IL-25, and IL-33, mediators known to activate type 2 innate immune responses, indicate that their neutralization does not result in AD improvement. Moreover, IL-5 is another type 2 cytokine involved in regulating eosinophil production and survival, although its blockade has not led to meaningful clinical benefits in patients with AD (David et al, 2023; Santamaria-Babí, 2022a). Collectively, this evidence reinforces the relevance of the adaptive immune response in AD and underscores the potential of CD4⁺ CLA⁺ memory T cells to reflect therapeutic success (Nicolàs et al, 2024).

NK cells may play a role in AD development and pathogenesis (Nomura and Kabashima, 2021) because they are recruited to inflamed tissues, including AD skin, where they display altered phenotypes and functions (Amand et al, 2017; Mack et al, 2020). In a recent study, patients with severe AD exhibited increased expression of CLA⁺ NK cells in both CD56^bright and CD56^dim subpopulations, indicating enhanced skin homing (de Lima et al, 2024). Functional studies revealed that CLA⁺ NK^dim cells respond strongly to bacterial stimuli (eg, staphylococcal enterotoxins) by producing inflammatory cytokines such as IFN-γ and TNF, highlighting their role in AD pathogenesis. In addition, severe AD skin lesions showed elevated levels of NK cell markers (pan-granzyme and NCAM-1/CD56), suggesting their involvement in perpetuating inflammation and itch through granzyme-mediated mechanisms. These findings support a potential role for NK cells in AD's inflammatory process, particularly in response to bacterial superantigens such as SEB, despite reduced peripheral NK cells (de Lima et al, 2024). Practically, these insights underscore the complexity of the immune dysregulation seen in AD and the importance of further exploring NK cells as therapeutic targets in AD management.

Staphylococcus aureus: a key player in CLA⁺ T-cell activation in AD

Staphylococcus aureus, implicated in microbial dysbiosis, skin barrier abnormalities, and T-cell–mediated inflammation, colonizes 90% of both lesional and nonlesional AD skin (Beck et al, 2023). This pathogen is closely associated with disease exacerbations and is linked to distinct phenotypic and endotypic profiles in patients with AD, particularly those with more severe disease (Clowry et al, 2024; Demessant-Flavigny et al, 2023; Edslev et al, 2020; Lipnharski et al, 2013; Simpson et al, 2018). S aureus expresses superantigens, such as SEB, which is the most prevalent in AD and associated with induction and severity of disease (Taskapan and Kumar, 2000). Through an IL-12–dependent mechanism, superantigens induce CLA expression on T cells, contributing to a population of memory T cells capable of migrating to lesional skin and perpetuating AD inflammation (Akdis et al, 1999; Taskapan and Kumar, 2000). This activation sustains inflammation through continuous T-cell activation and maintenance of lesional skin even in the absence of inciting allergens (Akdis et al, 1999; Taskapan and Kumar, 2000). Moreover, preferential skewing of S aureus–reactive TCR-Vβ expression is found on circulating CD4⁺ and CD8⁺ CLA⁺ T cells in patients with AD versus control (Davison et al, 2000). In cocultured models of AD lesional epidermal cells and circulating memory T cells, the activation of CLA⁺ T cells by SEB leads to the subsequent production of proinflammatory cytokines present in AD lesions, such as IL-4, IL-13, IL-17A, and IL-22 (Sans-De San Nicolàs et al, 2022). Thus, environmental factors notably influence CLA⁺ T-cell activation, particularly in the context of S aureus colonization, highlighting the interplay between microbial dynamics and immune responses in AD. Understanding these relationships, particularly in the context of CLA⁺ T-cell interactions, holds potential for developing targeted therapeutic strategies aimed at mitigating the impact of environmental triggers and pathogenic colonization on T-cell–mediated inflammation in AD. Recently, it has been shown that pediatric patients with S aureus cutaneous infections have a suppression of CLA⁺ Th17 and expansion of memory CLA⁺ IL-4⁺ IL-13⁺ (Th2) in circulation (Clowry et al, 2024).

Epigenetic modifications in CLA⁺ T cell: implications for AD pathogenesis

Epigenetic alterations have emerged as significant contributors to the pathogenesis of AD, particularly in the context of CLA⁺ T cells. Research indicates that these cells exhibit dysregulated epigenetic signatures that impact critical cytokine signaling pathways (Acevedo et al, 2020; Martin et al, 2020). Specifically, CD4⁺ CLA⁺ memory T cells in patients with AD show reduced DNA methylation in the upstream promoter region of the IL13 gene, correlating with increased IL13 mRNA expression and, thus, their ability for significant production of IL-13, a central pathogenic mediator in AD (Acevedo et al, 2020). In addition, Acevedo et al (2020) identified differential expression of 16 microRNAs that target genes involved in various biological processes, including critical immune and inflammatory pathways, such as cytokine signaling, MAPK signaling, and protein ubiquitination. These novel epigenetic insights further support the potential role of skin-homing CD4⁺ CLA⁺ memory T cells in mediating chronic inflammation in AD.

The connection between CLA⁺ T cells, AD biomarkers, and targeted therapies

Circulating CLA⁺ T cells are closely tied to several biomarkers and targeted therapies in AD, with implications for disease monitoring and treatment response. The search for reliable biomarkers in AD has identified over 100 candidates, with serum CCL17 emerging as the most reliable. CCL17 functions by binding to CCR4, a receptor preferentially expressed on circulating CD4⁺ CLA⁺ memory T cells (Renert-Yuval et al, 2021) and that has been shown to be central to AD pathogenesis (Biedermann et al, 2002). Increased CCL17 levels in the skin and serum correlate with AD severity and predict disease development, particularly in pediatric populations (Halling et al, 2023; Rinnov et al, 2023). RPT193 is a small-molecule antagonist of CCR4 that has demonstrated clinical efficacy in AD and improved lesional skin transcriptome expression of genes of Th1, Th2, and Th17/Th22 responses (Bissonnette et al, 2024), confirming the clinical relevance of CD4⁺ CLA⁺ CCR4⁺ T cells in AD pathogenesis. Similarly, CCL27, which attracts CLA+ T cells, is associated with disease severity and therapeutic response (Andersson et al, 2022).

A study with dupilumab, a neutralizing IL-4Ra biological agent that inhibits IL-4 and IL-13 binding, has demonstrated decreased production of IL-4, IL-13, and IL-22 in CD4⁺ CLA⁺ CCR4⁺ but not in CLA⁻ memory T cells after therapy. These circulating skin-homing cells appear to preferentially respond to IL-4RA blockade (Bakker et al, 2021), suggesting that they could serve as biomarkers for disease severity and therapy response. Recently, similar results have been reported for tralokinumab, an anti–IL-13–neutralizing therapy (Starrenburg et al, 2024).

Biomarker studies highlight CLA⁺ T cells’ ability to reflect AD immune profiles across different ages and ethnicities. As the search for a minimally invasive, reliable biomarker for AD is ongoing, CLA⁺ T cells are minimally invasive to measure and have been used to track therapeutic responses, including reductions in Th2 cytokines (IL-4, IL-5, IL-13, IL-22) with dupilumab. Moreover, the OX40–OX40L axis, prominent in CD4⁺ CLA⁺ T cells, supports the expansion of Th2 cells and correlates with disease severity, presenting another therapeutic target (Bakker et al, 2021; Croft et al, 2024).

IL-31, a neuroimmune cytokine predominantly produced by CLA⁺ Th2 cells, plays a critical role in pruritus, inflammation, and barrier dysfunction (Steinhoff et al, 2022). HDM-induced IL-31 production by CLA⁺ T cells correlates with pruritus intensity and plasma periostin levels; nemolizumab, a recently Food and Drug Administration (FDA)–approved treatment for AD, targets this pathway (Kwatra et al, 2023). In addition, Th2-high and Th2-low AD endotypes have been characterized, with CLA⁺ T cells distinguishing these groups through their differential cytokine responses, aiding in the stratification of therapeutic approaches (Sans-De San Nicolàs et al, 2022).

Circulating CLA+ T cells can also be affected by approved treatments for diseases other that AD. This is the case of mogamulizumab, a humanized mAb targeting CCR4 (a receptor highly expressed on certain CLA⁺ T-cell subsets, including Th2 cells, regulatory T cells [Tregs], and malignant T cells), demonstrating therapeutic potential (Beylot-Barry et al, 2023). Approved by the FDA for treating cutaneous T-cell lymphoma and Sézary syndrome in 2018, mogamulizumab’s ability to deplete CLA⁺ CCR4⁺ T cells highlights its relevance in addressing T-cell–mediated skin diseases (Amagai et al, 2022).

Role of CLA⁺ T cells in psoriasis

In comparison with AD, psoriasis pathogenesis depends on the IL-23/Th17 axis as it has been demonstrated by biological therapies. Circulating CLA⁺ memory T cells are involved in the autoimmune-driven pathogenesis of psoriasis, where Streptococcus pyogenes (Sp) throat infections play a pivotal role (Santamaria-Babí, 2022b). Tonsils of patients with psoriasis exhibit a higher frequency of CD4⁺ and CD8⁺ CLA⁺ T cells than those of healthy controls. In psoriasis, Sp-infected tonsils serve as a reservoir of Sp-specific CLA⁺ memory T cells with skin tropism. Interestingly, there is an identical TCRVβ gene rearrangement in memory T cells infiltrating psoriatic lesions and CLA⁺ T cells isolated from the tonsils of the same patients (Diluvio et al, 2006). Once in the skin, Sp-specific CLA⁺ T cells are believed to cross-react with certain keratins in the epidermis (Santamaria-Babí, 2022b). There is significant homology between streptococcal M protein and keratin. This finding suggests that an autoimmune process caused by molecular mimicry may contribute to the pathogenesis of psoriasis in some patients. Understanding the role of Sp in the production of IL-17A and IL-17F is crucial to elucidating the pathological mechanisms of psoriasis because these cytokines are key drivers of the disease.

Patients with psoriasis demonstrate elevated levels of IgA specific to Sp (IgA-Sp) in the absence of clinical tonsillitis or positive antistreptolysin O titers (De Jesús-Gil et al, 2020). Sp-induced CLA⁺ IL-17F production correlates with IgA-Sp levels, suggesting a coordinated immune response between skin-homing T cells and mucosal immunity (De Jesús-Gil et al, 2020). Interestingly, IgA-Sp in psoriasis predominantly belongs to the IgA1 subclass, characteristic of upper respiratory tract mucosa. This finding aligns with the tonsillar origin of the immune response and suggests a specialized role for CLA⁺ T cells and B cells in mediating IL-17 and IgA-Sp responses (Lilja et al, 1999; Pakkanen et al, 2010).

Candida albicans is also considered to be involved in psoriasis pathogenesis. The IL-23/Th17 axis governs the immune response to C albicans, with CLA⁺ T cells preferentially producing IL-17F and IL-17A in response to the fungus (de Jesús-Gil et al, 2021a). This dual role of IL-17 in providing protection against C albicans while driving psoriasis highlights the complex interplay of immune responses in the disease. Effective psoriasis treatments that inhibit IL-17 may inadvertently increase susceptibility to C albicans colonization, creating a potential vicious cycle. Plasma from patients with psoriasis shows increased levels of anti–C albicans IgA and IgG compared with that from healthy controls. C albicans cellular response is confined to CLA⁺ T cells and is primarily driven by the Th17 subset. In addition, the levels of anti–C albicans IgA are directly associated with CLA⁺ Th17 response in psoriasis.

Circulating CLA⁺ Tregs are also gaining interest because different lines of evidence support their involvement in psoriasis. For instance, circulating CLA⁺ Tregs are decreased in psoriasis and exhibit increased CCR7 expression along with reduced CLA expression. This altered phenotype suggests a reduced skin-homing capacity, which may lead to defective suppression of inflammation in lesional skin (Lee et al, 2024). Low-dose IL-2 immunotherapy is currently being evaluated in clinical studies and has demonstrated the ability to induce skin-homing CLA⁺ Tregs that migrate into the skin with suppressive capacity (Raeber et al, 2024). In comparison with AD, the relevance of circulating CLA⁺ memory T cells as biomarker useful for targeted therapies is poorly characterized and deserves further exploration.

The central role of skin-homing CD8⁺ CLA⁺ T cells in vitiligo pathogenesis

Vitiligo is the most prevalent autoimmune skin disorder characterized by depigmentation, affecting 0.5–2% of the population (Howitz et al, 1977; Taïeb and Picardo, 2007). It presents in 2 main clinical forms—segmental and nonsegmental/generalized—with the latter accounting for approximately 90% of cases (Rodrigues et al, 2017; Taïeb and Picardo, 2009).

The immunopathogenesis of vitiligo involves a complex interplay between innate and adaptive immunity, oxidative stress, and environmental triggers (Hlača et al, 2022). Circulating melanocyte-specific memory CD8⁺ CLA⁺ T cells contribute to melanocyte apoptosis, alongside additional mechanisms, leading to skin depigmentation seen in vitiligo (Boukhedouni et al, 2020). A study analyzing immune infiltrates in vitiligo skin revealed a key role for cytotoxic T cells in melanocyte destruction. Immunohistochemistry of lesional, perilesional, and nonlesional skin demonstrated increased infiltration of skin-homing CLA⁺ T cells, macrophages, and activated CD8⁺ T cells in perilesional areas. Strikingly, these T cells clustered around degenerating melanocytes, with ∼60% expressing granzyme B and perforin, indicating cytotoxic activity. Focal upregulation of HLA-DR and ICAM-1 in the epidermis at the site of melanocyte loss further supports immune-mediated melanocyte destruction. These findings underscore that skin-homing CD8⁺ T cells play a central role in the pathogenesis of vitiligo by targeting melanocytes through granule-mediated apoptosis (van den Wijngaard et al, 2000).

In a study that investigated the role of Tregs in suppressing CD8⁺ CLA⁺ T cells in patients with vitiligo with active and stable disease, results showed that in active vitiligo, Tregs exhibited reduced suppressive function compared with that in those with stable vitiligo and healthy controls. This impairment correlated with increased activation and proliferation of CD8⁺ CLA⁺ T cells. The findings suggest that dysfunction in Treg-mediated immune regulation contributes to the persistence and progression of vitiligo by failing to control pathogenic CD8⁺ T cells. These insights highlight a potential therapeutic target for restoring immune tolerance in vitiligo (Lin et al, 2014).

In a comprehensive flow cytometry study that compared T-cell polarization in the blood of patients with vitiligo compared with that patients with AD, psoriasis, and alopecia areata, results showed that in vitiligo, skin-homing/CLA⁺ and systemic/CLA⁻ T cells exhibited distinct cytokine polarization compared with that in controls and in those with other inflammatory skin diseases. IFN-γ–producing T cells were most elevated in vitiligo, alongside increased Th2, Th9, Th17, and IL-22–producing subsets, particularly in the CLA⁺ compartment. These findings underscore a unique multicytokine polarization in vitiligo, with CLA⁺ T cells playing a central role in its pathogenesis (Czarnowicki et al, 2019). This study and others (Martins et al, 2020) suggest that vitiligo is characterized by a plethora of immune axes activation, emphasizing the nuanced immunopathology of vitiligo and the potential for targeted therapeutic strategies.

Overall, CLA has emerged as more than just a skin-homing marker; it plays critical roles in the pathogenesis of inflammatory skin diseases, and it has been implicated at multiple levels of disease progression. In addition, CLA is gaining recognition as a valuable biomarker for disease monitoring and assessing therapeutic responses. Consequently, there is growing interest in targeting CLA⁺ skin-homing cells for the treatment of inflammatory skin conditions (Sernicola et al, 2020).

Knowledge gaps and future directions in the study of circulating CLA⁺ T cells in skin diseases

The study of CLA⁺ T cells has significantly advanced our understanding of their role in inflammatory skin diseases, but critical knowledge gaps remain. One prominent area of uncertainty is the functional heterogeneity within the CLA⁺ T-cell population. Although these cells are recognized as key drivers of skin inflammation, the distinct cytokine profiles and effector functions of CLA⁺ T-cell subsets in various inflammatory skin diseases are not fully delineated. Future studies employing single-cell RNA sequencing and proteomics could provide deeper insights into the functional diversity of these cells and elucidate how different subsets contribute to disease pathogenesis or resolution.

The precise molecular mechanisms governing the homing and retention of CLA⁺ T cells in the skin and their possible interaction with TRM cells also require further exploration. Although adhesion molecules and chemokine receptors such as E-selectin, CCR4, and CCR10 are known to play roles in skin-specific trafficking (Reiss et al, 2001; Soler et al, 2003), the relative contributions of these pathways in inflamed versus noninflamed skin remain unclear. In addition, the factors that ensure the retention of these cells in chronic inflammatory states versus their resolution during disease remission have not been fully characterized. Addressing these gaps could clarify the dynamics of CLA⁺ T-cell migration and retention in the skin.

Another critical gap lies in understanding the interactions between CLA⁺ T cells and the skin microenvironment. Although keratinocytes, dendritic cells, and other skin-resident immune cells are known to engage in crosstalk with CLA⁺ T cells, the functional outcomes of these interactions in different inflammatory diseases remain obscure. These interactions likely influence the initiation and perpetuation of skin inflammation and may play a role in maintaining homeostasis under healthy conditions.

Furthermore, although much of the current research focuses on the role of CLA⁺ T cells in diseases such as psoriasis and AD, their involvement in less studied conditions such as lichen planus and hidradenitis suppurativa is less explored. It is unclear whether disease-specific phenotypic or functional characteristics of CLA⁺ T cells exist, which could have implications for targeted therapies. Expanding the scope of research to include these conditions would provide a more comprehensive understanding of the role of CLA⁺ T cells across a broader spectrum of skin diseases.

Finally, the potential of CLA⁺ T cells as biomarkers and therapeutic targets warrants further investigation. Although preliminary studies suggest that these cells could serve as indicators of disease severity and treatment response, their reliability and practicality as biomarkers in clinical settings remain uncertain. Future studies should investigate the fluctuations of CLA⁺ T cells in the blood and skin in response to advanced treatments, including biologics and Jak inhibitors. In addition, therapeutically targeting CLA⁺ T-cell activity or migration raises important questions about balancing efficacy in reducing inflammation with preserving skin immune defenses. Longitudinal studies targeting CLA⁺ T cells could provide critical insights into their utility as biomarkers and their safety as therapeutic targets.

In conclusion, although significant progress has been made in understanding the role of CLA⁺ T cells in skin immunity and inflammation, critical gaps remain in our knowledge of their functional diversity, mechanisms of skin homing and retention, interactions with the skin microenvironment, and involvement across different diseases. Addressing these gaps will require innovative research approaches and will pave the way for new diagnostic and therapeutic strategies to better manage inflammatory skin diseases.

ORCIDs

Tali Czarnowicki: http://orcid.org/0000-0002-1157-5227

Lea Tordjman: http://orcid.org/0009-0000-5918-5853

Irene García-Jiménez: http://orcid.org/0000-0002-1769-354X

Luis F. Santamaria-Babí: http://orcid.org/0000-0002-1674-6654

Conflict of Interest

The authors state no conflict of interest.

corrected proof published online XXX