Ets1 represses Blimp1 to promote germinal center T follicular helper cell differentiation during viral infection.

Following acute viral infection, naïve CD4+ T cells differentiate into T helper 1 (Th1) and T follicular helper (Tfh) cells. The transcription factor Ets1 represses Tfh cell formation and function following protein immunization; however, whether Ets1 regulates Tfh differentiation in viral infection is unclear. Here, we demonstrate that during acute viral infection, conditional deletion of Ets1 in CD4+ T cells impairs germinal center (GC) Tfh differentiation and function, resulting in diminished GC B-cell responses, reduced IgG2c class switching, and impaired antibody production. Mechanistically, Ets1 deficiency results in aberrant upregulation of Blimp1 to negatively impact early Tfh and GC Tfh cell differentiation in a cell-intrinsic manner. Early Tfh differentiation is partially restored by knockdown of Blimp1 in Ets1-deficient T cells. In contrast, during protein immunization where Blimp1 is not highly expressed, Ets1 is not required to repress expression of CD25 and Blimp1 in early Tfh cells, and Ets1 deficiency results in a cell-intrinsic enhancement in GC Tfh differentiation. Collectively, these results demonstrate that Ets1 is a positive regulator of GC Tfh cell differentiation and function during viral infection, highlighting a context-dependent role for Ets1 in GC Tfh cell responses.