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.

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