TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

Abstract

Interleukin (IL)-17-producing CD8⁺ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ-producing effector CD8⁺ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (<i>Tcf7</i>) regulates CD8⁺ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1-driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8⁺ T cell subsets. IL-17-producing CD8⁺ T cells isolated from healthy humans were also distinct from CD8⁺IL-17^- T cells and enriched in pathways driven by <i>MAF</i> and <i>RORγt</i> Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.