ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor Bcl6

TLDR

The differentiation of follicular helper CD4⁺ T (Tfh) cells is poorly understood, with uncertainty about the minimal signals and timing required. The study shows that Tfh development begins immediately during dendritic‑cell priming and that ICOS induces Bcl6, which in turn drives CXCR5 expression. Using acute viral infection, the authors demonstrated that by day 2 after infection, CD4⁺ T cells bifurcate into Bcl6⁺ CXCR5⁺ Tfh cells and Blimp1⁺ Bcl6‑repressed effector Th cells, a process driven by ICOS signaling. Polarization into Bcl6⁺ Tfh and Blimp1⁺ effector Th cells was nearly complete by 72 h, but Tfh cells disappeared without B cells, indicating that B cells are required to maintain Bcl6 and Tfh commitment via sequential ICOS signals.

Abstract

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 Bcl6, and Bcl6 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: IL2Rαint cells expressed Bcl6 and CXCR5 (Tfh cell program), whereas IL2Rαhi cells exhibited strong Blimp1 expression that repressed Bcl6 (effector Th cell program). Virtually complete polarization between Bcl6+ 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 Bcl6 and Tfh cell commitment via sequential ICOS signals.