TGF-β specifies T <subscript>FH</subscript> versus T <subscript>H</subscript> 17 cell fates in murine CD4 <superscript>+</superscript> 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.