A virtual memory CD8 T cell-originated subset causes alopecia areata through innate-like cytotoxicity.

Virtual memory T (T) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although T cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a T cell-originated CD44CD49d CD8 T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8 T cells and can cause alopecia areata. Mechanistically, CD44CD49d CD8 T cells could be induced from conventional T cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44CD49d CD8 T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which T cells can cause chronic inflammatory disease by innate-like cytotoxicity.