Cross-presenting Langerhans cells are required for the early reactivation of resident CD8⁺ memory T cells in the epidermis

Tissue-resident memory CD8⁺ T cells (T_RM) reside at sites of previous infection, providing protection against reinfection with the same pathogen. In the skin, T_RM patrol the epidermis, where keratinocytes are the entry site for many viral infections. Epidermal T_RM react rapidly to cognate antigen encounter with the secretion of cytokines and differentiation into cytotoxic effector cells, constituting a first line of defense against skin reinfection. Despite the important protective role of skin T_RM, it has remained unclear, whether their reactivation requires a professional antigen-presenting cell (APC). We show here, using a model system that allows antigen targeting selectively to keratinocytes in a defined area of the skin, that limited antigen expression by keratinocytes results in rapid, antigen-specific reactivation of skin T_RM. Our data identify epidermal Langerhans cells that cross-present keratinocyte-derived antigens, as the professional APC indispensable for the early reactivation of T_RM in the epidermal layer of the skin.