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

Summary Activated CD4 T cells become either T-helper (Th) or T-follicular helper (Tfh) cells that support cellular or humoral immunity. We have investigated how polyclonal, vaccine induced T cells in mice bifurcate into Th1- and Tfh trajectories. We show that Th1 and Tfh cells originate from the same, highly proliferative precursor clones that co-express Th1- and Tfh-related transcription factors and chemokine receptors, including T-bet, BCL6, CXCR3 and CXCR5. Generation of the common Th1/Tfh precursor pool from antigen-specific CD4 T cells relies on CD28 costimulation but occurs independently of type-1 conventional dendritic cells (cDC1s) or B cells. Differentiation of Th1/Tfh precursors into the Th1 lineage relies on CD40 costimulation and cDC1s, while differentiation into the Tfh lineage relies on ICOS costimulation and B cells. Thus, activated CD4 T cells give rise to a bipotent Th1/Tfh precursor and differentiation into Th1 or Tfh cells depends on interactions with antigen-presenting cDC1s or B cells.