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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.

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