Requirements for development of T helper 1 and T follicular helper cells from a common precursor.

T helper (Th) and T follicular helper (Tfh) cells support cellular and humoral immunity, respectively. How activated CD4+ T cells commit to these fates remains unclear. Using a mouse vaccination model, we traced endogenous, polyclonal CD4+ T cells during bifurcation into Th1 and Tfh lineages. We found that Th1 and Tfh cells originate from shared, highly proliferative TCF1+SLAMF6+PD-1+ precursor clones that co-express Th1- and Tfh-related transcription factors and chemokine receptors, including T-bet, BCL6, CXCR3, and CXCR5. The generation of common Th1/Tfh precursors from naive CD4+ T cells requires CD28 costimulation but occurs independently of CD40, ICOS, and interaction with type 1 conventional dendritic cells (cDC1s) or B cells. Lineage commitment subsequently diverges: differentiation into Th1 cells relies on CD40 costimulation and cDC1s, whereas differentiation into Tfh cells requires ICOS costimulation and B cells. Activated CD4+ T cells thus give rise to a common Th1/Tfh precursor whose fate depends on interactions with distinct antigen-presenting cells.