Type I IFN-controlled Qa-2 expression identifies and maps the generation of Eomes⁺ thymic innate CD8 T cells

Innate CD8 T cells are a subset of CD8 lineage T cells that acquire proinflammatory effector functions during their development in the thymus. Yet the developmental mechanisms diverting them from conventional CD8 T cells remain incompletely understood. By mapping their developmental trajectory in the thymus, here we identify high-level expression of the nonclassical MHC-I molecule Qa-2 as a surface marker of innate CD8 T cells. Because Qa-2 expression is induced by type I interferon (IFN) signaling, these results further led us to uncover a role for tonic type I IFN signaling in their generation. Accordingly, interleukin-4 is considered both necessary and sufficient for this process, but innate CD8 T cell differentiation was also markedly impaired in the absence of type I IFN signaling, as documented with genetically engineered mice. Altogether, these findings report an intrathymic cytokine circuitry that orchestrates the differentiation of innate CD8 T cells during their thymic development.