Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8T cells in murine models of inflammation.

Abstract

The differentiation of naive CD8T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8T 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 CD8T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.