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J Exp Med. 2019 Jul 1;216(7):1682-1699. doi: 10.1084/jem.20181778. Epub 2019 May 29.

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

Author information

1
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
2
Department of Medical Biology, University of Melbourne, Parkville, Australia.
3
Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Australia.
4
Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
5
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.
6
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia.
7
Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia.
8
Centre for Future Landscapes, La Trobe University, Bundoora, Australia.
9
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.
10
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA.
11
Department of Clinical Immunology & Allergy, The Royal Melbourne Hospital, Parkville, Australia.
12
Department of Computing and Information Systems, University of Melbourne, Parkville, Australia.
13
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia belz@wehi.edu.au.

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.

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