TGF-β specifies T FH versus T H 17 cell fates in murine CD4 + T cells through c-Maf

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 H 17)–inducing conditions also yield separate CXCR5 + and IL-17A–producing cells, highlighting shared and distinct cell fate trajectories of T FH and T H 17 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 H 17 cells share a common developmental stage, and that c-Maf acts as a switch factor for T FH versus T H 17 cell fates in TGF-β–rich environments in vitro and in vivo.