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.