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

T follicular helper (T) cells are essential for protective antibody responses. Histone modifications direct T 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 HK 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 T cells and had diminished germinal center and antibody responses. Mechanistically, KMT2D sustained T responses in part by promoting Thpok and Il21 expression through HKMe deposition at gene enhancers. Consistent with loss of THPOK, KMT2D-deficient CD4 T cells acquired a cytotoxic CD4 T (CD4) cell phenotype involving elevated expression of RUNX3, EOMES, and cytolytic molecules. Our findings show KMT2D balances T development and humoral immunity over CD4 cells.