The circulating precursor cells that give rise to human resident memory T cells (T _RM ) are poorly characterized. We used an in vitro differentiation system and human skin–grafted mice to study T _RM generation from circulating human memory T cell subsets. In vitro T _RM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4 ⁺ T cells and granzyme B production in CD8 ⁺ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (T _EM ) had the highest conversion rate to T _RM in vitro and in vivo, but central memory T cells (T _CM ) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of T _RM . In summary, T _CM are highly efficient precursors of human skin T _RM , a feature that may underlie their known association with effective long-term immunity.

Tissue-resident memory T cells (T_RM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although T_RM originate from circulating T cells, T_RM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin T_RM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8⁺ T_RM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin T_RM are available to date, psoriatic skin T_RM are affected in the current treatments of psoriasis. Targeting skin T_RM or using T_RM as a potential index for disease severity can be an attractive strategy in psoriasis.

Recent studies have highlighted that human resident memory T cells (T_RM) are functionally distinct from circulating T cells. Thus, it can be postulated that skin T cells age differently from blood-circulating T cells. We assessed T-cell density, diversity, and function in individuals of various ages to study the immunologic effects of aging on human skin from two different countries. No decline in the density of T cells was noted with advancing age, and the frequency of epidermal CD49a⁺ CD8 T_RM was increased in elderly individuals regardless of ethnicity. T-cell diversity and antipathogen responses were maintained in the skin of elderly individuals but declined in the blood. Our findings demonstrate that in elderly individuals, skin T cells maintain their density, diversity, and protective cytokine production despite the reduced T-cell diversity and function in blood. Skin resident T cells may represent a long-lived, highly protective reservoir of immunity in elderly people.

Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2–related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.