KMT2D coordinates antiviral CD4+ T cell responses through opposing effects on T follicular helper and cytotoxic gene expression.

T follicular helper (TFH) cells are essential for protective antibody responses. Histone modifications direct TFH development and function; however, the role of specific chromatin modifiers in this process is not well understood. Lysine methyltransferase 2D (KMT2D) is a histone methyltransferase that acts at H3K4 to promote gene expression. Herein, we examined the contribution of KMT2D to T cell responses during acute lymphocytic choriomeningitis virus infection. Mice lacking KMT2D in T cells generated sufficient antiviral CD8+ T cell responses to resolve infection. However, these mice formed fewer TFH cells and had diminished germinal center and antibody responses. Mechanistically, KMT2D sustained TFH responses in part by promoting Thpok and Il21 expression through H3K4Me1 deposition at gene enhancers. Consistent with loss of THPOK, KMT2D-deficient CD4+ T cells acquired a cytotoxic CD4+ T (CD4CTL) cell phenotype involving elevated expression of RUNX3, EOMES, and cytolytic molecules. Our findings show KMT2D balances TFH development and humoral immunity over CD4CTL cells.