The Transcription Factor YY-1 Is an Essential Regulator of T Follicular Helper Cell Differentiation

T follicular helper (T_FH) cells are a specialized subset of CD4 T cells that deliver critical help signals to B cells for the production of high-affinity Abs. Understanding the genetic program regulating T_FH differentiation is critical if one wants to manipulate T_FH cells during vaccination. A large number of transcription factor (TFs) involved in the regulation of T_FH differentiation have been characterized. However, there are likely additional unknown TFs required for this process. To identify new TFs, we screened a large short hairpin RNA library targeting 353 TFs in mice using an in vivo RNA interference screen. Yin Yang 1 (YY-1) was identified as a novel positive regulator of T_FH differentiation. Ablation of YY-1 severely impaired T_FH differentiation following acute viral infection and protein immunization. We found that the zinc fingers of YY-1 are critical to support T_FH differentiation. Thus, we discovered a novel TF involved in the regulation of T_FH cells.