Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX

Sexually dimorphic immune responses are evident by increased susceptibility of males to viral infections. Interestingly, our results indicate that while males possess more natural killer (NK) cells, they display impaired effector function. These differences are attributed to lower male expression of X-linked UTX, an epigenetic regulator which escapes X-inactivation in females. NK cell-specific heterozygous deletion of UTX in females recapitulated male NK cell phenotypes of increased NK cells and defective effector function. Notably, mice with NK cell-intrinsic UTX deficiency show increased lethality to mouse cytomegalovirus. Integrative UTX CUT&Tag, ATAC-seq and RNA-seq analysis revealed a critical role for UTX in regulating the chromatin landscape and expression at gene loci involved in NK cell homeostasis and effector function. Collectively, these data implicate UTX as a molecular determinant of sex differences in NK cell homeostasis and effector function and suggest enhancing UTX as a strategy to boost endogenous NK effector responses. Bulk RNA-seq and ATAC-seq on wild type or UTX-deficient mouse NK cells following viral infection CUT&Tag followed by Illumina sequencing