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

T follicular helper (T_FH) cells are essential for protective antibody responses. Histone modifications direct T_FH 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 T_FH cells and had diminished germinal center and antibody responses. Mechanistically, KMT2D sustained T_FH 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 (CD4^CTL) cell phenotype involving elevated expression of RUNX3, EOMES, and cytolytic molecules. Our findings show KMT2D balances T_FH development and humoral immunity over CD4^CTL cells.