The Chromatin Regulator Mll1 Supports T Follicular Helper Cell Differentiation by Controlling Expression of Bcl6, LEF-1, and TCF-1

T follicular helper (T-FH) cells are essential for developing protective Ab responses following vaccination. Greater understanding of the genetic program leading to T-FH differentiation is needed. Chromatin modifications are central in the control of gene expression. However, detailed knowledge of how chromatin regulators (CRs) regulate differentiation of T-FH cells is limited. We screened a large short hairpin RNA library targeting all known CRs in mice and identified the histone methyltransferase mixed lineage leukemia 1 (Mll1) as a positive regulator of T-FH differentiation. Loss of Mll1 expression reduced formation of T-FH cells following acute viral infection or protein immunization. In addition, expression of the T-FH lineage-defining transcription factor Bcl6 was reduced in the absence of Mll1. Transcriptomics analysis identified Lef1 and Tcf7 as genes dependent on Mll1 for their expression, which provides one mechanism for the regulation of T-FH differentiation by Mll1. Taken together, CRs such as Mll1 substantially influence T-FH differentiation.