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

Abstract

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^loLy6C^-, CD5^hiLy6C^-, and CD5^hiLy6C⁺ cells. CD5^hiLy6C⁺ cells differ from CD5^loLy6C^- and CD5^hiLy6C^- cells in terms of gene expression profiles and functional properties. Moreover, CD5^hiLy6C⁺ 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^hiLy6C⁺ 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.