Anatomy and Neuroscience - Research Publications

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

Mielke, LA ; Liao, Y ; Clemens, EB ; Firth, MA ; Duckworth, B ; Huang, Q ; Almeida, FF ; Chopin, M ; Koay, H-F ; Bell, CA ; Hediyeh-Zadeh, S ; Park, SL ; Raghu, D ; Choi, J ; Putoczki, TL ; Hodgkin, PD ; Franks, AE ; Mackay, LK ; Godfrey, D ; Davis, MJ ; Xue, H-H ; Bryant, VL ; Kedzierska, K ; Shi, W ; Belz, GT (ROCKEFELLER UNIV PRESS, 2019-07)

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.