Self-reactivity controls functional diversity of naive CD8(+) T cells by co-opting tonic type I interferon

The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8(+) T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5(lo)Ly6C(–), CD5(hi)Ly6C(–), and CD5(hi)Ly6C(+) cells. CD5(hi)Ly6C(+) cells differ from CD5(lo)Ly6C(–) and CD5(hi)Ly6C(–) cells in terms of gene expression profiles and functional properties. Moreover, CD5(hi)Ly6C(+) cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5(hi)Ly6C(+) cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8(+) T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8(+) T cells by co-opting tonic type I interferon signaling.