Developmental self-reactivity determines the pathogenic Tc17 differentiation potential of naive CD8+ T cells by adjusting endogenous SMAD3 expression

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 inflammatory disease models. The differential ability of Tc17 differentiation was not related to T-cell receptor (TCR) diversity and antigen specificity but was inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon was linked to differential levels of intrinsic TCR sensitivity and basal 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. Overall design: To investigate the genomic characteristics of the three different naive CD8+ T cell subsets, CD5low Ly6C-, CD5hi Ly6C-, and CD5hi Ly6C+, we cultured each subset in Tc17 polarizing condition. We then perfomed gene expression profiling analysis using data obtained from RNA-seq of each subset.