The Role of Tissue Resident Memory Cells in Immunodermatological Disorders

ABSTRACT

Tissue‐resident memory T cells (TRMs) are a distinct memory T‐cell subset that permanently reside in tissues such as the skin. In chronic immune‐mediated dermatoses, including psoriasis, atopic dermatitis, and vitiligo, TRMs are implicated in site‐specific “disease memory,” contributing to persistence and relapse at previously affected sites. This review synthesizes emerging concepts on TRMs in chronic inflammatory skin diseases and discusses clinical and translational implications, including TRM‐targeted therapies. Original human, animal, or in vitro studies evaluating TRMs in the pathogenesis or persistence of dermatologic diseases were included. In psoriasis, CD8⁺ TRMs (CD69⁺CD103⁺) persisted in clinically healed skin. For atopic dermatitis, both CD4⁺ and CD8⁺ TRMs are implicated in maintaining Th2/Th22 inflammation. In vitiligo, autoreactive CD8⁺ TRMs at lesional margins mediate melanocyte destruction. Across dermatological diseases, TRMs share three core features: persistence in previously affected skin after clinical resolution, rapid reactivation by diverse triggers (stress, autoantigens, allergens, or cytokines) leading to site‐specific recurrence, and relative resistance to conventional therapies. Together, these properties provide a unifying framework linking tissue immune memory to the chronic, relapsing nature of inflammatory skin diseases. However, the dominant TRM pathways vary by disease, reflecting differences in immune polarization and antigen specificity. Targeting TRMs represents a promising strategy for disease control and serves as a biomarker of residual disease or flare.

Tissue‐resident memory T cells (TRMs) persist in previously affected skin after clinical resolution, acting as reservoirs of disease memory. Upon reactivation by inflammatory triggers, TRMs drive relapse through disease‐specific cytokine pathways. Targeting TRM survival or function represents a promising strategy for durable control of chronic inflammatory dermatoses.

1. Introduction

In the past decade, tissue‐resident memory T cells (TRMs) have emerged as a key contributor to the pathogenesis of various immunodermatological disorders, notably psoriasis, vitiligo, and atopic dermatitis. These conditions are often characterized by well‐demarcated lesions and a characteristic propensity for recurrence at the same sites after treatment cessation. This suggests a localized immunological memory. Under physiological conditions, TRMs serve as non‐recirculating, long‐lived sentinel cells that provide rapid immune responses against pathogens at a barrier site. However, these cells may become dysregulated in disease and drive chronic or relapsing inflammation by providing site‐specific memory. Lesional skin in these immunodermatological disorders often shows a dense infiltration of pro‐inflammatory TRMs. These findings suggest that TRM cells act as reservoirs of disease memory, underscoring their potential as therapeutic targets given their role in disease persistence and relapse [1]. It was suggested that by modulating TRM functions, we may achieve durable disease control or even remission in chronic immune‐mediated skin conditions [2]. This review integrates disease‐specific TRM populations with their clinical consequences, highlighting their role in relapse and treatment resistance across major dermatologic disorders.

2. Development, Phenotype, and Function of Tissue‐Resident Memory T Cells

TRM cells are a special subset of long‐lived, non‐recirculating memory T cells that provide a rapid defense response at peripheral barrier sites. These are found in both CD4⁺ and CD8⁺ lineages. TRMs are modified by local microenvironmental factors and therefore exhibit tissue‐specific heterogeneity [3] (Figure 1).

FIGURE 1.

Phenotypic and functional characteristics of CD8⁺ and CD4⁺ TRM cells in chronic inflammation and disease relapse. Figure summarizing the key surface markers, survival signals, chemokine receptors, and effector functions of CD8⁺ and CD4⁺ TRM cells within peripheral tissues. CD8⁺ TRM cells (left) express residency markers CD69 and CD103, along with CD49a and CD44, and are maintained by local cytokines including IL‐15, IL‐7, and TGF‐β. Their activation is regulated by costimulatory (CD27, CD28) and inhibitory (PD‐1, CTLA‐4) receptors, while CXCR3 and CXCR6 direct localization within inflamed tissue niches, enabling rapid production of TNF‐α and IL‐17 upon reactivation. CD4⁺ TRM cells (right) share core residency markers and chemokine receptors, rely on IL‐15, IL‐2, and IL‐7 for survival, and display a polyfunctional cytokine profile dominated by IFN‐γ, IL‐17, and IL‐22. Collectively, the schematic highlights how distinct yet overlapping TRM phenotypes sustain local immune memory, drive pathogenic recall responses, and contribute to disease persistence and relapse.

The origin of TRM cells is not fully understood. Studies suggest they can develop from naïve T cells, central memory (TCM), effector memory (TEM), or memory precursor effector cells (MPECs), guided by local signals like TGF‐β, IL‐7, and IL‐15 [4]. TCMs usually reside in secondary lymphoid organs. TEMs enter inflamed peripheral tissues as effector immune cells. In contrast, TRMs persist at tissue sites and do not re‐enter circulation [5].

Key genes and surface markers help control how TRM cells form and stay active in the skin. Surface markers such as CD69 and CD103 are commonly used to identify TRMs. Among these two markers, CD69 prevents TRM cells from leaving the tissue by blocking S1PR1 signaling, whereas CD103 helps them remain at epithelial sites by binding to E‐cadherin [6]. TRMs also express tissue‐specific homing molecules, including CLA, CCR4, and CXCR3, in the skin [1].

Transcription factors such as Hobit, Runx2/3, Blimp‐1, AhR, and Bhlhe40 help regulate how TRM cells develop, remain in tissues, and function. Bhlhe40 is especially important for maintaining mitochondrial health, which is needed for cytokine production. Without Bhlhe40, TRM cells have weaker mitochondria and produce less IFN‐γ, although this can be partially mitigated by metabolic support. CD8⁺ TRM cells can quickly respond when reactivated by producing IFN‐γ and granzyme B [7]. CD49a and CD103 are key markers of epidermal CD8⁺ TRMs. CD4⁺ TRMs, though less defined, may depend more on antigen persistence and have been implicated in tissue regeneration and immune memory. Memory T cells are divided into circulating and non‐circulating (tissue‐resident) memory T cells. Circulating memory T cells in blood and lymphoid organs can be classified into central memory T cells (TCM) and effector memory T cells (TEM). TRM cells reside in non‐lymphoid tissues such as the skin, lungs, brain, and intestines, providing rapid local immune responses to pathogens [8].

3. TRMs and Psoriasis

TRMs have emerged as pivotal mediators of immunopathogenesis, treatment failure, and recurrence in psoriasis. Despite clinical resolution with conventional and targeted therapies, TRMs persist in both lesional and non‐lesional skin and retain the ability to produce pathogenic cytokines such as IL‐17A, IL‐22, and IFN‐γ [9, 10]. Among these, epidermal CD8⁺ CD103⁺ TRMs have been most strongly linked to the reappearance of psoriatic lesions, highlighting their role as reservoirs of immunological memory that sustain chronic disease [11, 12].

Although both CD4⁺ and CD8⁺ TRM cells persist within the epidermis after clinical resolution of psoriasis, they exhibit distinct cytokine profiles that contribute differently to disease persistence and relapse. Cheuk et al. first demonstrated that epidermal CD8⁺ CD103⁺ TRM cells predominantly produce IL‐17A following ex vivo stimulation, consistent with a T17 phenotype, whereas epidermal CD4⁺ TRM cells preferentially secrete IL‐22, characteristic of Th22 cells [11]. These findings were further supported by Strobl and Haniffa, who showed that IL‐17A‐producing CD8⁺ CD103⁺ CD49a⁻ TRM cells express CCR6, while IL‐22 production is largely confined to CD4⁺ TRM cells; both populations are predominantly αβTCR‐expressing cells that remain resident in clinically healed lesions [13]. Functionally, IL‐22 drives keratinocyte hyperproliferation, acanthosis, and abnormal epidermal differentiation, whereas IL‐17A reinforces local inflammatory signaling. Acting together, these cytokines recreate the epidermal alterations that define psoriatic plaques. Notably, the persistence of IL‐22‐producing CD4⁺ TRM cells, together with prolonged epigenetic programming, enables a rapid pathogenic response upon re‐exposure to inflammatory stimuli, thereby predisposing previously affected skin to relapse [14].

The IL‐17/IL‐23 axis provides critical support for TRM maintenance and function. IL‐17A, the most abundant and biologically active cytokine in psoriatic lesions, is central to disease pathology. However, while IL‐17 inhibitors effectively clear plaques, they have a limited impact on TRM survival, which may explain the frequent relapses observed after treatment discontinuation. Again, IL‐23 plays a critical role in sustaining TRM populations via in situ proliferation [15, 16].

Matsumura et al. showed that IL‐17A–producing CD8⁺ TRMs in non‐lesional skin and circulating IL‐17A–producing CD8⁺ ex‐TRMs increased with longer disease duration, suggesting progressive expansion of these pathogenic populations with chronic psoriasis. In the same study, IL‐23 inhibition, but not IL‐17A inhibition, was associated with reductions in IL‐17A–producing CD8⁺ TRMs in both lesional and non‐lesional skin, as well as circulating IL‐17A–producing CD8⁺ ex‐TRMs [17]. These findings are consistent with earlier evidence demonstrating enrichment of IL‐23 receptor–expressing CD103⁺ CD8⁺ TRMs in resolved psoriasis and the role of IL‐23 in promoting pathogenic IL‐17A–producing CD8⁺ T cells [11, 18]. Collectively, these translational data suggest that IL‐23 blockade may influence pathogenic TRM populations differently from IL‐17A inhibition, although the clinical significance of these immunologic changes and their impact on long‐term disease remission require further investigation.

Early intervention in psoriasis is increasingly recognized as critical for achieving optimal outcomes, as immune‐mediated diseases tend to be more responsive before chronic inflammation becomes entrenched. The GUIDE study is a multicenter, randomized phase IIIb trial that evaluated the benefits of initiating guselkumab, an IL‐23 inhibitor, in patients with short disease duration (≤ 2 years) versus those with longer‐standing disease. Notably, patients with early disease showed superior results: 51.8% achieved complete skin clearance (Psoriasis Area and Severity Index [PASI] = 0) by Week 28, and 43.7% were classified as “super responders” (sustained PASI = 0 at Weeks 20 and 28), compared to 39.4% and 28.1%, respectively, in the long‐duration group. Time to response was also shorter in early treated patients, and logistic regression identified shorter disease duration and no prior biologic use as the strongest predictors of robust outcomes [19].

Beyond clinical efficacy, the study highlighted immunological shifts driven by guselkumab. By Week 4, significant reductions in IL‐17A, IL‐17F, IL‐22, and β‐defensin 2 were observed across both groups [19] However, the greater immunologic benefit seen with early treatment likely reflects IL‐23's role in sustaining pathogenic TRMs. These cells accumulate over time and contribute to relapse, making them harder to target in chronic diseases. Mehta et al. demonstrated that, unlike IL‐17A inhibitors, guselkumab reduces TRM populations in healed psoriatic skin 6 months after treatment initiation, suggesting its potential not only to control symptoms but also to modify disease memory and promote sustained remission [16].

Even after histological resolution, TRM‐associated cytokines and molecular scars remain in the skin, differing by treatment modality [20] Circulating TRM‐like CD8⁺ CCR10⁺ T cells are enriched in psoriatic arthritis (PsA) and exhibit a Tc2/22 phenotype, indicating a systemic extension of TRM function from skin to joint inflammation [21]. A transcriptional program suppressing Th17/Tc17 activity is lost in psoriatic TRMs. Resolved lesions contain IL‐17A/F dual‐producing T cells and dormant TRMs, identifying them as possible drivers of relapse [22].

Additional insights into TRM heterogeneity come from Japanese studies identifying a PD‐1–expressing subset of epidermal CD8⁺ CD103⁺ TRMs. These cells correlate with disease severity, express IL‐23R, and produce IL‐17A, whereas PD‐1–negative CD8⁺ CD103⁺ TRMs preferentially produce IFN‐γ. Distinct TCR usage patterns further suggest functional specialization within TRM subsets, with PD‐1 expression delineating a highly pathogenic population that may amplify local inflammation and contribute to treatment resistance [10].

Clinically, the persistence of TRMs explains hallmark features of psoriasis, including chronicity, relapse in the same anatomical sites, and the Koebner phenomenon. Localized disease memory is reflected in lesion recurrence at scar sites, while systemic koebnerization, such as widespread flaring after trauma, such as tattooing, highlights the broader role of TRMs in maintaining immunological memory across skin compartments [23] (Figure 2 and Table S1).

FIGURE 2.

Role of tissue‐resident memory T cells in psoriasis pathogenesis and relapse. Figure depicting the immunological continuum from clinical resolution to lesion reactivation and established psoriatic plaque, emphasizing the central role of TRM cells. Healed skin retains long‐lived CD8⁺ and CD4⁺ TRM cells within the epidermis and dermis, constituting a localized disease memory despite clinical remission. Upon exposure to environmental triggers, activation of cutaneous dendritic cells and IL‐23 signaling rapidly reactivates resident TRM cells, with recruitment of circulating central and effector memory T cells and amplification of Th17 responses. In fully developed plaques, activated TRM cells expressing residency markers (CD69, CD103, CD49) produce IL‐17, IL‐22, and IFN‐γ, driving keratinocyte hyperproliferation and sustained inflammation, further augmented by neutrophil and lymphocyte influx. Overall, the schematic underscores TRM cells as key mediators of psoriatic disease memory, relapse, and chronicity, supporting therapeutic targeting of the IL‐23/IL‐17 axis and resident immune cell compartments.

4. TRMs and Vitiligo

Vitiligo is a chronic autoimmune skin condition characterized by the destruction of melanocytes, resulting in depigmented patches. Although repigmentation can be achieved with various treatments, relapse at the same sites remains common. Regulatory T (Treg) cells are reduced in number and function in vitiligo, with impaired suppressive capacity, decreased FOXP3 and IL‐10 expression, and increased IL‐17 and IL‐22 levels, supporting a loss of immune tolerance. These findings implicate Treg dysfunction in vitiligo pathogenesis and highlight Treg‐directed immunomodulation as a potential therapeutic strategy [24].

Recent studies show that CD8⁺ TRMs play a major role in disease persistence and recurrence, making them key drivers in vitiligo pathogenesis. Boniface et al. showed that active and stable vitiligo lesions are rich in CD8⁺ TRMs (CD69⁺ CD103⁺), mainly in the epidermis. These cells produce IFN‐γ and TNF‐α and remain primed for rapid response. They also express CXCR3, which is linked to tissue homing and site‐specific relapse [25]. Richmond et al. showed that IL‐15 is essential for TRM survival and activation. TRMs express the IL‐15 receptor subunit CD122, while keratinocytes present IL‐15 via CD215. Blocking IL‐15 with anti‐CD122 antibodies reduced IFN‐γ production, depleted TRMs from lesions, and achieved lasting repigmentation in mice. These findings provide proof of concept that targeting the IL‐15/TRM axis may be a promising therapeutic strategy for vitiligo, although its efficacy and long‐term benefit in humans remain to be established [26].

Subsequent work by the same group highlighted the cooperative role of TRMs and circulating TCMs in maintaining disease activity. TRMs drive local persistence, whereas TCMs exacerbate inflammation by releasing chemokines such as CXCL9 and CXCL10. Blocking TCM trafficking with FTY720 or depleting TCMs using a Thy1.1 antibody reversed the disease, suggesting that disrupting TRM–TCM interactions could lead to long‐term remission [27]. CD49a is a key integrin that supports TRM survival. While it is not needed for initial T cell migration or positioning, it boosts TRM persistence, dendritic shape, and IFN‐γ response. Induced by TGF‐β and IL‐12, CD49a acts as both a marker and a functional enhancer of TRM immunity [28]. Janus kinase (JAK) inhibitors improve vitiligo without removing TRM cells, suggesting their effect comes from blocking cytokine activity rather than eliminating the TRM cells. This highlights the persistence and resilience of TRMs even with strong systemic treatments [29].

Patients with generalized vitiligo (GV) have more CD4⁺ and CD8⁺ TRMs across all skin areas but significantly fewer TRM‐Tregs and antigen‐specific Tregs. This imbalance allows TRMs to act unchecked, producing high levels of IFN‐γ and granzyme B, while regulatory cytokines like IL‐10 and TGF‐β are reduced. These changes indicate that TRM‐Treg dysfunction drives melanocyte destruction and contributes to treatment resistance [30].

Melanocyte‐specific CD8⁺ CD49a⁺ TRMs persist and remain active after systemic corticosteroid therapy, continuing to produce IFN‐γ and granzyme B, thereby making them resistant to immunosuppression and a major cause of lesion relapse. These long‐lived, antigen‐specific TRMs remain functionally primed even in clinically resolved skin, driving disease recurrence and treatment resistance. However, long‐term remission likely requires approaches that both suppress TRM function and reduce their persistence, such as disrupting the TRM–TCM axis, restoring Treg control, and modulating cytokines like IL‐10, TGF‐β, and IL‐15. Precision therapies targeting melanocyte‐reactive TRMs, particularly CD49a⁺ subsets, may hold the key to durable repigmentation in vitiligo [31, 32] (Table S2).

5. TRMs and Atopic Dermatitis

Over the last decade, research has increasingly shown that TRM cells, especially CD4⁺ and CD8⁺ subsets expressing CD103 and CD69, play a central role in atopic dermatitis (AD) by driving local inflammation and mediating disease memory, thereby contributing to both flares and chronicity. Single‐cell RNA sequencing reveals that lesional AD skin contains abundant TRM cells, inflammatory dendritic cells, and cytokine‐producing T cells, supported by COL6A5⁺COL18A1⁺ fibroblasts that release chemokines such as CCL2 and CCL19 to attract and organize immune cells. The expansion of TRMs producing IL‐13 and IL‐22 further contributes to the type 2‐skewed inflammation observed in AD [33].

TRMs persist in resolved AD skin despite IL‐4Rα blockade with dupilumab, remaining functional and alarmin‐responsive (IL‐25, IL‐33, TSLP) for up to a year [34]. These memory cells create a rapid‐response network that may explain frequent disease relapse after treatment discontinuation. Similarly, CD4⁺ TRMs have been shown to produce IFN‐γ and TNF‐α upon re‐exposure to allergens, promoting neutrophil recruitment and driving flares in a mouse model of recurrent AD. CXCR4⁺ natural killer T (NKT) cells, which share TRM‐like features, also contribute to allergic inflammation in AD by clustering with CXCL12⁺ fibroblasts, thereby creating stable inflammatory niches [35]. This highlights the role of skin‐resident immune cells beyond classical TRMs.

Notably, therapeutic attempts to deplete TRMs face challenges. While corticosteroids can transiently inhibit TRM reactivation, they fail to prevent TRM formation or persistence and may even exacerbate flare severity through altered hapten clearance [36, 37].

Bakker et al. demonstrated that dupilumab rapidly and sustainably inhibited IL‐4Rα signaling and reduced the number of proliferating, Th2/Th22 cytokine‐producing, circulating skin‐homing (CLA+/CCR4+) CD4⁺ T cells without altering the overall proportion of skin‐homing T‐cell subsets. These findings suggest that dupilumab suppresses the functional activity of pathogenic T cells destined for the skin; however, the study did not directly evaluate TRM cells [38].

Further, CD4⁺ TRMs are increasingly implicated in adult AD, where they are enriched in lesional skin and associated with upregulation of inflammation‐related genes such as SBNO2 and FOXO1. These genes are associated with Th1 infiltration and are downregulated in keratinocytes in response to inflammatory cytokines, suggesting a potential regulatory role in TRM‐mediated inflammation [39]. Additionally, follicular and peripheral helper T cells (Tfh/Tph), monocyte‐derived dendritic cells (Mo‐DCs), and TRMs coordinate in lesional skin to sustain disease severity [40]. Staphylococcus aureus can directly trigger AD‐like skin inflammation through innate immune pathways and establish bacteria‐specific TRM cells that drive both protective immunity and pathogenic flares [41].

Nishimura et al. performed single‐cell RNA sequencing on skin samples from patients with atopic dermatitis 16 weeks before, after, and 1 year after dupilumab treatment to investigate changes in TRM subsets. Dupilumab treatment shifted TRM populations from predominantly cytotoxic CD8⁺ cells in untreated skin to CD4⁺ and mixed subsets, with a marked reduction in cytotoxic gene expression and overall cytotoxicity over time. These changes were accompanied by increased expression of IL‐13 and TGFB1 and persistence of GATA3‐positive cells, indicating that while dupilumab reduces pathogenic cytotoxic TRM activity and promotes tissue‐repair features, ongoing type 2 signals may necessitate prolonged therapy for complete resolution of inflammation in AD [42].

Overall, accumulating evidence supports an important role for TRMs in maintaining disease memory and chronic inflammation in AD. Although preclinical and translational studies suggest that targeting TRM survival, function, or interactions with the skin microenvironment may represent a promising therapeutic strategy, additional clinical studies are needed to determine whether these approaches translate into sustained remission or reduced relapse in patients with AD (Table S3).

6. TRMs and Contact Dermatitis, and Contact Sensitization

The ability of the TRM cells to elicit rapid, localized immune responses makes them essential in barrier immunity. However, in allergic contact dermatitis (ACD), a T‐cell‐mediated delayed‐type hypersensitivity, TRM cells are now recognized as major contributors to disease chronicity, recurrence, and local immunopathology.

TRM cells mediate robust, long‐lasting localized recall responses to allergens, with markedly higher immune reactivity at previously sensitized sites compared to naïve skin areas. CD8⁺ TRM cells producing IL‐17A and IFN‐γ amplify keratinocyte IL‐1β responses, intensifying local inflammation [43]. After allergen exposure, CD8⁺ CD69⁺ CD103⁺ TRM cells replace dendritic epidermal T cells (DETCs) as the dominant population in the epidermal niche. In a mouse model, the magnitude of the allergic reaction correlated with the number of CD8⁺ epidermal TRM cells, which, in turn, showed a direct relationship with allergen dose and the frequency of allergen exposures [44].

In mouse models (BALB/c model) of contact hypersensitivity, healed skin exhibited local skin memory (LSM), with both CD4⁺ and CD8⁺ TRM cells inducing flare‐up reactions upon re‐exposure. Notably, CD8⁺ TRM cells decline over time, whereas CD4⁺ TRM cells can persist for prolonged periods, suggesting a potentially sustained role for CD4⁺ subsets in maintaining long‐term cutaneous immune memory [45].

Dendritic epidermal γδ T cells (DETCs), through IFN‐γ sensing and PD‐L1 expression, modulate CD8⁺ TRM expansion and function. Mice deficient in DETCs or IFN‐γ receptor on γδ T cells demonstrate hyperactive TRM responses and aggravated inflammation [46]. These findings highlight a critical crosstalk between innate and adaptive skin‐resident T cells in maintaining immune homeostasis.

In a mouse model of ACD, clinically relevant allergens were shown to induce epidermal CD8⁺ TRM cells that drive flare‐up reactions by releasing CXCL1/CXCL2 and recruiting neutrophils. The magnitude of these responses correlated with the number of CD8⁺ TRM cells and was enhanced by CD4⁺ T‐cell depletion. These findings indicate that pathogenic CD8⁺ TRM cells mediate allergen‐induced inflammation, normally restrained by anti‐inflammatory CD4⁺ T cells [47].

Topical corticosteroids (TCS), such as triamcinolone acetonide, can suppress inflammation but fail to prevent TRM formation or eradicate existing TRM populations. Their inability to maintain long‐term tolerance stems from the persistence and reactivation potential of TRMs upon treatment withdrawal [39].

Initial TRM generation occurs independently of TCR signaling; however, long‐term maintenance is antigen dependent. Persistent antigen presence fosters selective expansion of specific TCR clonotypes, reinforcing the chronic inflammatory cycle [48]. This provides a rationale for strategies such as allergen avoidance and antigen‐targeted immunomodulation in chronic ACD.

Overall, available evidence supports a central role for TRM cells in shaping localized immune memory and recurrent inflammation in ACD. While experimental studies suggest that modulation of TRM survival, function, or antigen‐specific activation may be beneficial, translating these approaches into durable clinical remission remains to be established and requires further investigation [46, 47] (Table S4).

7. Shared and Divergent Features of TRMs Across Dermatologic Diseases

Across the dermatological conditions discussed, TRMs share three fundamental properties. First, they persist within previously affected skin, even after lesions have clinically resolved. Second, they can be reactivated by various triggers such as stress, autoantigens, allergens, or cytokines, leading to recurrence at the same anatomical sites. Third, they often resist conventional treatments. Together, these features, persistence, reactivation, and treatment resistance, provide a unifying conceptual framework that connects underlying immunological mechanisms with the hallmark clinical patterns of chronic inflammatory skin diseases. Despite these shared features, the dominant TRM axis varies across diseases, reflecting differences in immune polarization and antigen specificity.

Although TRM cells are central to disease persistence across inflammatory skin disorders, their dominant effector pathways vary with the underlying immunology. In psoriasis, IL‐23‐dependent IL‐17‐producing TRM cells sustain chronic inflammation and site‐specific relapse, highlighting the potential of early IL‐23 blockade to modify disease course. Vitiligo is characterized by antigen‐specific, IFN‐γ‐producing cytotoxic CD8⁺ TRM cells that mediate melanocyte destruction, suggesting that therapeutic strategies should target TRM survival or promote their depletion. Atopic dermatitis is driven by Th2‐polarized TRM cells that persist despite clinical improvement, supporting the need for sustained immune suppression to maintain remission. Conversely, ACD is dominated by allergen‐specific TRM cells that rapidly initiate recall responses upon re‐exposure, underscoring the importance of allergen avoidance alongside anti‐inflammatory therapy. Together, these findings demonstrate that while TRM cells represent a shared mechanism of local immune memory, their functional polarization, antigen specificity, and therapeutic strategies are disease‐dependent, emphasizing the need for tailored TRM‐directed treatment (Table S5).

8. TRMs and Other Immuno‐Dermatological Disorders

TRM cell involvement in systemic sclerosis (SSc) appears fundamentally distinct from other chronic dermatoses. Koguchi‐Yoshioka et al. demonstrated that lesional skin in SSc patients exhibits a marked reduction in CD69⁺ CD103⁺ TRM cells, despite active T‐cell infiltration. This points to a selective defect in TRM generation or maintenance. Potential mechanisms include an inhospitable tissue microenvironment due to fibrosis, aberrant IL‐15/TGF‐β signaling, or intrinsic T‐cell dysfunction. This TRM deficiency might impair local immune surveillance, facilitating persistent fibrosis [49]. The failure to establish a stable TRM population in SSc contrasts with their pathological persistence in diseases such as psoriasis and atopic dermatitis and may represent both a diagnostic biomarker and a therapeutic target.

Complementary evidence underscores the persistent clonal expansion of CD4⁺ and CD8⁺ T cells with antigen‐driven TCR specificity over the years. The reduced TCR diversity and clustering of TCRβ sequences suggest chronic antigenic stimulation in SSc, reinforcing the hypothesis that T‐cell autoreactivity, possibly in the absence of effective TRM regulation, drives disease pathology [48].

Recent studies have identified a subset of PSGL1^lo^CD4⁺ TRM cells enriched in graft‐versus‐host disease (GVHD) target tissues. These cells exhibit high expression of PD‐1, ICOS, and IL‐21, hallmarks of B‐cell helper T‐cell function. They are non‐circulating, express CD69 (a TRM marker), and reside in close proximity to memory B cells in both humanized mouse models and GVHD patient tissues. Functionally, these TRM cells drive B‐cell differentiation into plasma cells and facilitate autoantibody production via PD‐1/PD‐L2 interaction. Their persistence and tissue‐localized activity position them as critical effectors in chronic GVHD‐associated autoimmunity and potential targets for tissue‐selective therapies [50, 51].

TRM cells play pivotal roles in severe cutaneous adverse drug reactions such as DRESS (drug reaction with eosinophilia and systemic symptoms) and SJS/TEN (Stevens‐Johnson syndrome/toxic epidermal necrolysis). Trubiano et al. demonstrated that CD8⁺ and CD4⁺ TRMs persist long after clinical resolution of drug‐induced reactions. Intradermal rechallenge with the causative drug induced TRM‐dominated inflammation, confirming localized immune memory [52]. Recent data identified heightened expression of chemokine receptors (CCR8 and CXCR3) and their ligands (CCL1 and CXCL10) in patients with prolonged DRESS, suggesting sustained TRM activation via chemotactic signaling. Elevated levels of cytotoxic CD8⁺ memory cells and IgG autoantibodies reinforce an autoimmune element in chronic DRESS, with JAK inhibitors showing therapeutic efficacy by attenuating these chemokine axes [53].

SJS/TEN is driven by massive recruitment and expansion of cytotoxic CD8⁺ TRMs and circulating CD8⁺ T cells, accompanied by a diminished Treg signature, which contributes to severe epidermal necrolysis. DRESS, in contrast, retains a hybrid profile with both recruited cytotoxic T cells and preserved regulatory T cells, suggesting more complex immune regulation [54].

There is compelling evidence of phenotypic plasticity between cytotoxic TRMs (cTRMs) and central memory T cells (TCMs) in fixed drug eruption (FDE). Recurrent lesions harbor CD49a⁺ (IFN‐γ–producing) cTRMs and CCR7⁺ TCMs, primarily in the CD8⁺ subset. TCR sequencing revealed substantial overlaps between cTRMs and skin TCMs, but minimal overlap with circulating TCMs, suggesting that lesional TRMs can transition into TCM‐like phenotypes within the skin. This plasticity may underlie the hallmark recurrence of FDE at fixed sites upon re‐exposure to the drug. These findings underscore the localized nature of memory responses in FDE and suggest the therapeutic potential of disrupting the TRM‐to‐TCM transition to prevent lesion recurrence [55].

Recent studies have suggested a possible role of TRM cells in alopecia areata (AA). AA lesions are enriched for CD8⁺ tissue‐resident memory T cells (TRMs; CD69⁺ CD103⁺), especially near the peribulbar area. These long‐lived, non‐recirculating cells are of cytotoxic phenotype and produce IFN‐γ and granzyme B. They are anchored to the epithelium with the help of CD69 (by blocking S1PR1) and CD103 (by binding E‐cadherin), implicating them as direct mediators of follicular injury and drivers of relapse. Lesions also exhibit an increased number of CD11c⁺ dendritic cells. Clinically, TRM counts (CD103⁺ CD69⁺) rise after stopping JAK inhibitors and are associated with disease recurrence. The extent to which these cells directly drive relapse in humans remains to be fully clarified [56, 57].

Recent work has identified a disease‐causing CD8⁺ T‐cell subset in alopecia areata with tissue‐residency features. These cells are CD44^super‐high^ CD49d^low^ and arise from virtual memory (TVM) T cells that look “memory‐like” despite no prior foreign‐antigen exposure. This subset is functionally distinct from conventional CD8⁺ TVM cells and can cause AA. Their pathogenic activity is mediated by NKG2D‐dependent innate‐like cytotoxicity. Its differentiation from TVM is driven by IL‐12, IL‐15, and IL‐18. IL‐15 further boosts NKG2D signaling, helping to trigger disease onset [58].

TRM involvement in AA opens new therapeutic options. IL‐23–dependent signaling has been implicated in the maintenance and proliferation of skin TRM17 cells, suggesting that cytokine‐targeted approaches may modulate these populations. However, whether such strategies can effectively alter TRM‐mediated disease activity or reduce relapse rates in patients with AA remains to be determined [57] (Table S6).

9. Conclusion and Outlook

This review aimed to synthesize current evidence regarding the role of TRM cells in immunodermatological diseases. As understanding of cutaneous TRMs has rapidly evolved, emerging data increasingly implicate these cells in the pathogenesis of chronic skin disorders such as psoriasis, vitiligo, and atopic dermatitis. Our review revealed that the included studies used heterogeneous criteria to define TRMs, employing varying combinations of surface markers and localization patterns within the skin. While most studies predominantly investigated CD8⁺ TRM populations, the functional significance and distribution of CD4⁺ TRMs in the skin remain less well elucidated.

Several methodological limitations were apparent across the literature, including variability in TRM characterization, limited exploration of TRM function in non‐cutaneous tissues, and a heavy reliance on murine models, which may limit direct translational applicability to human disease. Nonetheless, a key finding across multiple studies is the long‐lived nature of TRM cells, which, while potentially contributing to disease persistence and recurrence, also presents opportunities for targeted therapeutic intervention. Notably, in psoriasis, early‐phase research suggests that strategies aimed at depleting or modulating TRMs may offer the possibility of sustained remission, with disease modification or even functional cure currently under investigation.

From a clinical perspective, TRM biology is beginning to shape therapeutic strategies. IL‐23 blockade in psoriasis, IL‐15 inhibition in vitiligo, and emerging approaches such as metabolic interference, Kv1.3 modulation, or local TRM depletion provide proof of concept that targeting tissue memory can prolong remission. TRM monitoring may also serve as a biomarker platform to guide treatment duration, predict flare risk, and personalize therapy choices. Future clinical trials should incorporate TRM readouts (e.g., skin biopsy‐based TRM density, circulating ex‐TRMs, transcriptional signatures) to evaluate residual disease activity beyond visible remission.

In conclusion, this review underscores the central role of TRM cells in the chronicity and recurrence of immune‐mediated skin diseases and highlights their considerable therapeutic potential. With further research, TRMs may emerge not only as biomarkers of disease activity but also as pivotal targets in the development of durable, tissue‐specific immunotherapies. Modulating TRM function may represent a transformative strategy in the management of chronic inflammatory dermatoses.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Summary of key studies on TRMs in psoriasis, highlighting their roles and associated clinical implications.

Table S2: Summary of the evidence of Tissue‐Resident Memory T Cells in vitiligo.

Table S3: Summary of the evidence of Tissue‐Resident Memory T Cells in atopic dermatitis.

Table S4: Summary of the evidence of Tissue‐Resident Memory T Cells in contact dermatitis.

Table S5: Summary of the disease‐specific dominant TRM axes and their clinical implications in dermatologic disorders.

Table S6: Summary of the evidence of Tissue‐Resident Memory T Cells in Miscellaneous Immuno‐Dermatological Disorders.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.