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

• Published in: Science immunology 2024-03, Vol.9 (93), p.eadd4818
• Main Authors: Chang, Yinshui, Bach, Luisa, Hasiuk, Marko, Wen, Lifen, Elmzzahi, Tarek, Tsui, Carlson, Gutiérrez-Melo, Nicolás, Steffen, Teresa, Utzschneider, Daniel T, Raj, Timsse, Jost, Paul Jonas, Heink, Sylvia, Cheng, Jingyuan, Burton, Oliver T, Zeiträg, Julia, Alterauge, Dominik, Dahlström, Frank, Becker, Jennifer-Christin, Kastl, Melanie, Symeonidis, Konstantinos, van Uelft, Martina, Becker, Matthias, Reschke, Sarah, Krebs, Stefan, Blum, Helmut, Abdullah, Zeinab, Paeschke, Katrin, Ohnmacht, Caspar, Neumann, Christian, Liston, Adrian, Meissner, Felix, Korn, Thomas, Hasenauer, Jan, Heissmeyer, Vigo, Beyer, Marc, Kallies, Axel, Jeker, Lukas T, Baumjohann, Dirk
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.add4818

T follicular helper (TFH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse TFH 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 TFH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4+ T cells in vitro. TGF-β-induced mouse CXCR5+ TFH cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated TFH 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 (TH17)-inducing conditions also yield separate CXCR5+ and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of TFH and TH17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced TFH cell program, that TFH and TH17 cells share a common developmental stage, and that c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-β-rich environments in vitro and in vivo.T follicular helper (TFH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse TFH 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 TFH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4+ T cells in vitro. TGF-β-induced mouse CXCR5+ TFH cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated TFH 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 (TH17)-inducing conditions also yield separate CXCR5+ and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of TFH and TH17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced TFH cell program, that TFH and TH17 cells share a common developmental stage, and that c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-β-rich environments in vitro and in vivo.