ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor BcI6

The nature of follicular helper CD4(+) T (Tfh) cell differentiation remains controversial, including the minimal signals required for Tfh cell differentiation and the time at which Tfh cell differentiation occurs. Here we determine that Tfh cell development initiates immediately during dendritic cell (DC) priming in vivo. We demonstrate that inducible costimulator (ICOS) provides a critical early signal to induce the transcription factor BcI6, and BcI6 then induces CXCR5, the canonical feature of Tfh cells. Strikingly, a bifurcation between Tfh and effector Th cells was measurable by the second cell division of CD4(+) T cells, at day 2 after an acute viral infection: IL2R alpha(int) cells expressed BcI6 and CXCR5 (Tfh cell program), whereas IL2R alpha(hi) cells exhibited strong Blimp1 expression that repressed BcI6 (effector Th cell program). Virtually complete polarization between BcI6(+) Tfh cells and Blimp1(+) effector Th cell populations developed by 72 hr, even without B cells. Tfh cells were subsequently lost in the absence of B cells, demonstrating a B cell requirement for maintenance of BcI6 and Tfh cell commitment via sequential ICOS signals.