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The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses. The heterogeneity in naive CD8+ T cells is essential for diverse immune responses. Here the authors show that variations in developmental self-reactivity of CD8+ T cells influence their differentiation into Tc17 cells in inflammatory conditions. [ABSTRACT FROM AUTHOR]

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, CD5loLy6C–, CD5hiLy6C–, and CD5hiLy6C+ cells. CD5hiLy6C+ cells differ from CD5loLy6C– and CD5hiLy6C– cells in terms of gene expression profiles and functional properties. Moreover, CD5hiLy6C+ 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 CD5hiLy6C+ 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. [ABSTRACT FROM AUTHOR]