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-hiCD49d^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-hiCD49d^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.