Langerhans Cells Directly Interact with Resident T Cells in the Human Epidermis

Adult human skin contains nearly twice as many T cells as the peripheral blood, which include tissue-resident memory T (TRM) cells. However, the precise mechanisms maintaining TRM cells in the healthy skin remain unclear. Using normal human skin samples, we find that Langerhans cells (LCs) contact T cells in the epidermis of the elderly. LCs with high human leukocyte antigen (HLA)-II, CD86, and PD-L2 expression directly contacted PD-1 + TRM cells and CTLA-4 + regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, ultraviolet B radiation and hapten, downregulated HLA-II and CD86 on LCs in the epidermis, suggesting that disruption of LC-T cell tolerogenic axis contributes to skin inflammation. Interestingly, immune checkpoint blockade therapy was associated with decreased epidermal LC-T cell contact in the normal skin of cancer patients affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.