Human epidermal resident memory T cells: beyond the dermal perspective

The concept of tissue-resident memory T (T_RM) cells has fundamentally transformed our understanding of peripheral immune surveillance. Although skin T_RM biology has been extensively studied, most investigations have focused on the dermis, whereas the epidermis has traditionally been regarded primarily as a physical barrier composed predominantly of keratinocytes. However, accumulating evidence has demonstrated that the normal human epidermis harbors abundant populations of resident T cells, including both conventional and regulatory T_RM cells, indicating that the epidermis is a highly specialized immunological compartment. In this review, we summarize current knowledge regarding the origin, composition, phenotype, and dynamics of human epidermal T_RM cells, with particular emphasis on studies performed in human tissues. Epidermal T_RM cells are enriched for CD8⁺CD69⁺CD103⁺ populations and include specialized cytotoxic subsets expressing CD49a and CD101, whereas regulatory T_RM cells constitute a distinct epithelial regulatory network that contributes to local immune tolerance. We also discuss recent advances demonstrating that epidermal T_RM cells actively patrol the epidermis, interact closely with Langerhans cells, and participate in the maintenance of epidermal immune homeostasis. Furthermore, emerging evidence implicates epidermal T_RM cells in a variety of human diseases, including HIV infection, fixed drug eruption, vitiligo, and alopecia areata. Collectively, these findings support a model in which conventional T_RM cells, regulatory T_RM cells, Langerhans cells, and keratinocytes form an integrated epidermal immune ecosystem that balances immune surveillance and immune regulation. Recognition of this cellular network challenges the traditional dermis-centric view of cutaneous immunity and suggests that the epidermis should be regarded as an autonomous immunological compartment. A deeper understanding of epidermal immune organization may provide new insights into the pathogenesis and treatment of epidermis-centered diseases.