Human epidermal resident memory T cells: beyond the dermal perspective.

The concept of tissue-resident memory T (TRM) cells has fundamentally transformed our understanding of peripheral immune surveillance. Although skin TRM 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 TRM 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 TRM cells, with particular emphasis on studies performed in human tissues. Epidermal TRM cells are enriched for CD8+CD69+CD103+ populations and include specialized cytotoxic subsets expressing CD49a and CD101, whereas regulatory TRM cells constitute a distinct epithelial regulatory network that contributes to local immune tolerance. We also discuss recent advances demonstrating that epidermal TRM cells actively patrol the epidermis, interact closely with Langerhans cells, and participate in the maintenance of epidermal immune homeostasis. Furthermore, emerging evidence implicates epidermal TRM 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 TRM cells, regulatory TRM 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.