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. Virtual memory T cells have antimicrobial functions but whether they can contribute to inflammatory pathology is unclear. Here the authors show that a subset of CD8(+) T cells that originates from virtual memory T cells upon cytokine stimulation can drive the chronic inflammatory disease alopecia areata via innate-like cytotoxic effector functions.