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

Virtual memory T (T VM ) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although T VM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a T VM cell-originated CD44 super-high(s-hi) CD49d lo CD8 + T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8 + T VM cells and can cause alopecia areata. Mechanistically, CD44 s-hi CD49d lo CD8 + T cells could be induced from conventional T VM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44 s-hi CD49d lo 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 VM cells can cause chronic inflammatory disease by innate-like cytotoxicity.