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

Lisa A. Mielke, Yang Liao, Ella Bridie Clemens, Matthew A. Firth, Brigette Duckworth, Qiutong Huang, Francisca F. Almeida, Michael Chopin, Hui Fern Koay, Carolyn A. Bell, Soroor Hediyeh-Zadeh, Simone L. Park, Dinesh Raghu, Jarny Choi, Tracy L. Putoczki, Philip D. Hodgkin, Ashley E. Franks, Laura K. Mackay, Dale I. Godfrey, Melissa J. DavisHai Hui Xue, Vanessa L. Bryant, Katherine Kedzierska, Wei Shi, Gabrielle T. Belz

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)1682-1699
Number of pages18
JournalJournal of Experimental Medicine
Volume216
Issue number7
DOIs
Publication statusPublished - Jul 2019
Externally publishedYes

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