TGF-β Specifies T Versus T17 Cell Fates in Murine CD4 T Cells Through C-Maf

T follicular helper (T) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T 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 hallmark molecules CXCR5 and Bcl6 in activated mouse CD4 T cells in vitro. TGF-β-induced mouse CXCR5 T cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated T 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 (T17)-inducing conditions also yield separate CXCR5 and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of T and T17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced T cell program, that T and T17 cells share a common developmental stage, and that c-Maf acts as a switch factor for T versus T17 cell fates in TGF-β-rich environments in vitro and in vivo.