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Ezh2 is an histone methyltransferase (HMT) that catalyzes H3K27me3 and functions in T H 1, T H 2, and Treg cells primarily via HMT activity. Here we show that Ezh2 ablation impairs T follicular helper (T FH ) cell differentiation and activation of the T FH  transcription program. In T FH  cells, most Ezh2-occupied genomic sites, including the  Bcl6  promoter, are associated with H3K27ac rather than H3K27me3. Mechanistically, Ezh2 is recruited by Tcf1 to directly activate  Bcl6  transcription, with this function requiring Ezh2 phosphorylation at Ser21. Meanwhile, Ezh2 deploys H3K27me3 to repress  Cdkn2a  expression in T FH  cells, where aberrantly upregulated p19Arf, a  Cdkn2a  protein product, triggers T FH  cell apoptosis and antagonizes Bcl6 function via protein-protein interaction. Either forced expression of Bcl6 or genetic ablation of p19Arf in Ezh2-deficient cells improves T FH  cell differentiation and helper function. Thus, Ezh2 orchestrates T FH -lineage specification and function maturation by integrating phosphorylation-dependent transcriptional activation and HMT-dependent gene repression.

Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf