The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection

Epigenetic modifications to histones dictate the differentiation of naïve CD4 + T cells into different subsets of effector T helper (T H ) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of T H 1, T H 2 and regulatory T (T reg ) cells. However, whether and how EZH2 regulates follicular helper T (T FH ) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific T FH cells compared to those in T H 1 cells. Ablation of EZH2 in LCMV-specific CD4 + T cells leads to a selective impairment of early T FH cell fate commitment, but not late T FH differentiation or memory T FH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for T FH fate commitment, particularly B cell lymphoma 6 (Bcl6) , and thus directs T FH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early T FH differentiation during acute viral infection.