TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf

Yinshui Chang, Luisa Bach, Marko Hasiuk, Lifen Wen, Tarek Elmzzahi, Carlson Tsui, Nicolás Gutiérrez-Melo, Teresa Steffen, Daniel T Utzschneider, Timsse Raj, Paul Jonas Jost, Sylvia Heink, Jingyuan Cheng, Oliver T Burton, Julia Zeiträg, Dominik Alterauge, Frank Dahlström, Jennifer-Christin Becker, Melanie Kastl, Konstantinos Symeonidis, Martina van Uelft, Matthias Becker, Sarah Reschke, Stefan Krebs , Helmut Blum, Zeinab Abdullah, Katrin Paeschke, Caspar Ohnmacht, Christian Neumann, Adrian Liston, Felix Meissner, Thomas Korn, Jan Hasenauer, Vigo Heissmeyer, Marc Beyer, Axel Kallies, Lukas T Jeker, Dirk Baumjohann (2024 Mar 1) TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf. Sci Immunol 9(93):eadd4818. doi: 10.1126/sciimmunol.add4818 (Projects A03, B06, B12)

Abstract cited directly from the article:

T follicular helper (T_FH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T_FH cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor–β (TGF-β) induces robust expression of T_FH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4⁺ T cells in vitro. TGF-β–induced mouse CXCR5⁺ T_FH cells are phenotypically, transcriptionally, and functionally similar to in vivo–generated T_FH cells and provide critical help to B cells. The study further reveals that TGF-β–induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-β–containing T helper 17 (T_H17)–inducing conditions also yield separate CXCR5⁺ and IL-17A–producing cells, highlighting shared and distinct cell fate trajectories of T_FH and T_H17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β–induced T_FH cell program, that T_FH and T_H17 cells share a common developmental stage, and that c-Maf acts as a switch factor for T_FH versus T_H17 cell fates in TGF-β–rich environments in vitro and in vivo.