Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8⁺ T cells in murine models of inflammation

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.