Tissue-Resident Memory T Cells Explain Site-Specific Relapse in Atopic Dermatitis

Atopic dermatitis (搜索)搜索该疾病 (AD) is one of the most prevalent chronic inflammatory skin diseases, affecting up to 20% of children and approximately 10% of adults worldwide, with a steadily increasing incidence in industrialized regions. According to the Global Burden of Disease Study 2021, approximately 129 million individuals were affected by AD in 2021, with projections estimating an increase to 148 million cases by 2050. A striking clinical feature of the disease is the recurrence of lesions at identical anatomical sites even after apparent clinical resolution, a phenomenon that points directly to a localized form of residual disease memory.

A narrative review published in Frontiers in Immunology synthesizes current evidence implicating tissue-resident memory T (TRM) cells as the central cellular substrate of this residual disease memory. The authors argue that TRM biology provides a unifying immunological framework linking residual inflammation, site-specific relapse, and treatment resistance in AD.

The Biology of Tissue-Resident Memory T Cells

TRM are long-lived, non-circulating lymphocytes embedded within peripheral tissues such as the skin, where they maintain local immune programs and enable rapid recall responses. Human skin harbors distinct epidermal and dermal TRM subsets. Epidermal TRM are predominantly CD8+ and characterized by high expression of CD103, which anchors them to keratinocytes, while dermal TRM are more frequently CD4+ and often lack CD103 expression. In AD, pathogenic CD4+ CD103+ TRM populations have been observed that bridge these anatomical compartments and are potent producers of IL-4, IL-13 and IL-22, driving both barrier dysfunction and chronic pruritus.

The persistence of TRM cells depends on both intracellular programs and external interactions with the skin microenvironment. Intracellular factors such as Hobit, Blimp-1, and Runx3 maintain cells in a "ready" effector state, while surface markers including CD69, CD103, and CD49a secure physical retention in epithelial niches. TRM cells also exhibit metabolic adaptation, shifting energy consumption toward fatty acid uptake and mitochondrial oxidative phosphorylation. T-cell receptor sequencing reveals that identical clonotypes are maintained in resolved AD lesions for months, constituting a stable "molecular trace" of disease memory.

Beyond intrinsic programming, TRM persistence is reinforced by continuous dialogue with surrounding non-immune cells. Keratinocytes, fibroblasts, and hair follicle cells secrete IL-7 and IL-15 (搜索)搜索该靶点, which are indispensable for TRM homeostatic proliferation and long-term viability. Chronic barrier disruption stimulates the release of epithelial interleukins including IL-25, IL-33, and TSLP, creating a self-perpetuating inflammatory loop that strengthens the existing TRM population.

Relapse After Treatment Withdrawal

Despite substantial therapeutic advances, relapse after treatment discontinuation remains a hallmark of AD management. Dupilumab查看药品详情, a monoclonal antibody targeting IL-4 receptor α, has demonstrated robust efficacy in moderate-to-severe AD. However, the SOLO-CONTINUE study showed that patients switched from maintenance dupilumab to placebo gradually lost disease control, with EASI-75 maintained by 30.4% on placebo versus 71.6% with continued dupilumab. The time to first loss of IGA 0/1 was a mean of 57 days in the placebo group compared to 114 days with continued dupilumab.

JAK inhibitors provide rapid suppression of inflammatory signaling and pruritus, yet withdrawal studies consistently demonstrate early disease recurrence. In the REGIMEN study, discontinuation or dose reduction of abrocitinib查看药品详情 increased flare probability, with a median time to flare of about 28 days. Similar findings were reported for upadacitinib查看药品详情, with pruritus worsening within approximately 5 days and loss of skin response within approximately 4 weeks after discontinuation.

For tralokinumab查看药品详情, long-term extension studies demonstrated that among responders reassigned to placebo, tralokinumab maintained an IGA 0/1 score in 34.0% and an EASI-75 score in 26.4% at week 52. Similar patterns were observed with lebrikizumab查看药品详情, with maintenance of IGA 0/1 in 47.9% and EASI-75 in 66.4%.

The authors note that the withdrawal kinetics of these targeted therapies, ranging from days for JAK inhibitors to weeks or months for biologics, reflect the temporal dynamics of residual TRM reactivation rather than purely pharmacokinetic wash-out.

Targeting Disease Memory

Amlitelimab查看药品详情, targeting the OX40–OX40L (搜索)搜索该靶点 axis, represents a distinct approach aimed at modulating pathogenic T-cell memory. OX40 expression on skin-homing memory T cells has been demonstrated in AD. In the STREAM-AD phase 2b trial, 57.0% of patients who discontinued amlitelimab retained an IGA 0/1 score, whereas 61.6% maintained EASI-75. The authors describe amlitelimab as a clinically advanced strategy with potential memory-modulating effects, rather than a TRM-eradicating therapy, as available evidence does not demonstrate selective depletion or permanent reprogramming of pathogenic TRM cells.

Other biologically plausible targets include survival cytokines such as IL-15 (搜索)搜索该靶点, which supports the maintenance and long-term survival of TRM cells. Studies on vitiligo show that blocking the IL-15/CD122 axis reduces autoreactive TRM activity and contributes to more durable disease control, though IL-15 targeting in AD remains a hypothesis rather than an established therapeutic strategy.

The authors caution that adhesion and retention pathways such as CD69, CD103, and CD49a are not disease-specific and play important roles in protective immune surveillance, including antimicrobial and antitumor responses at barrier sites. Accordingly, broad inhibition of TRM retention could compromise beneficial barrier immunity. Instead, they suggest that modulating the tissue niches that support pathogenic TRM persistence—including keratinocyte-derived IL-7 and IL-15 (搜索)搜索该靶点, chemokines, epithelial alarmins, and stromal signals—may be a better strategy than directly eliminating TRM cells.

Toward Durable Remission

The review concludes that TRM constitute a central cellular substrate of residual disease memory in AD and provide a mechanistic explanation for site-specific relapse and treatment resistance. Therapeutic strategies that selectively modulate pathogenic TRM and their supporting microenvironment, while preserving protective barrier immunity, may be required to achieve durable remission.

Several methodological challenges complicate TRM research in humans, including limited standardization of marker definitions, phenotypic plasticity of resident populations, and reliance on cross-sectional biopsy analyses. The authors emphasize that integrative approaches combining surface phenotyping with transcriptomic, epigenetic, and clonal analyses, as well as advances in single-cell and spatial multi-omics, longitudinal sampling, and clonotype tracking, are expected to refine TRM classification and improve reproducibility. TRM also represent potential biomarkers for relapse risk and therapeutic responsiveness, particularly given the emerging concept of circulating TRM-like ("ex-TRM") populations.