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

There is heterogeneity in the response to self-ligands within the naive CD8(+) T cell pool and the consequences of this are unclear. Here the authors show subsets of naive CD8(+) T cells which differ in expression of Ly6C and CD5 and response to viral infection through regulation by type I IFN signalling. 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.