LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6

Follicular helper T cells (T FH cells) are specialized effector CD4 + T cells that help B cells develop germinal centers and memory. Crotty and colleagues show that the transcription factors LEF-1 and TCF-1 are required for early T FH differentiation. Follicular helper T cells (T FH cells) are specialized effector CD4 + T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T FH cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T FH cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T FH cells and the formation of GCs. Forced expression of LEF-1 enhanced T FH differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4 + T cells to T FH cell signals. Second, they promoted early T FH differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.