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

Abstract

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.