LEF-1 and TCF-1 orchestrate T follicular helper cell differentiation by regulating differentiation circuits upstream of Bcl6

T follicular helper (T(FH)) cells are specialized effector CD4(+) T cells that help B cells develop germinal centers and memory. However, the transcription factors that regulate T(FH) differentiation remain incompletely understood. Here we report that selective loss of either Lef1 (LEF-1) or Tcf7 (TCF-1) resulted in T(FH) defects, while deletion of Lef1 and Tcf7 severely impaired T(FH) differentiation and germinal centers. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated T(FH) differentiation by two general mechanisms. First, they established the responsiveness of naïve CD4(+) T cells to T(FH) signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of IL-6Rα and gp130, enhancing ICOS expression, and promoting expression of Bcl6.