LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor BcI6

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 ICE-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 LEE-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-61R alpha and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor BcI6.