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

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 (Tcf7) 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 MAF and RORγt. 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.