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 cells. However, the precise mechanisms maintaining tissue-resident memory T 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 HLA-II, CD86, and PD-L2 expression directly contacted PD-1⁺ tissue-resident memory T cells and CTLA-4⁺ regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, UVB 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 patients with cancer affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.