Epigenetic modifications to histones dictate the differentiation of naïve CD4 T cells into different subsets of effector T helper (T) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of T1, T2 and regulatory T (T) cells. However, whether and how EZH2 regulates follicular helper T (T) 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 cells compared to those in T1 cells. Ablation of EZH2 in LCMV-specific CD4 T cells leads to a selective impairment of early T cell fate commitment, but not late T differentiation or memory T maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for T fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs T cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early T differentiation during acute viral infection.
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