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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-beta (TGF-beta) induces robust expression of T-FH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4(+) T cells in vitro. TGF-beta-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-beta-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-beta-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-beta-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-beta-rich environments in vitro and in vivo.