Sex Differences in NK Cells Mediated by the X-linked Epigenetic Regulator UTX

Luke Riggan; Joey Li; rana Tafti; Scott Chin; Feiyang Ma; Matteo Pellegrini; timothy O'Sullivan; Maureen Su

Abstract Text: Viral infection outcomes are sex-biased, with males generally more susceptible to human cytomegalovirus (HCMV) and other viral infections compared to females. These differences may reflect sexual dimorphism in immune cell composition and function. As such, it is surprising that numbers of natural killer (NK) cells, a first line of anti-viral defense, are increased in males compared to females. Here we show in mouse models and human samples that while males harbor increased NK cell numbers, they concomitantly produce less IFN-γ, a key proinflammatory cytokine for NK-mediated effector responses. This difference is not due solely to divergent levels of gonadal hormones, since these differences persist even with gonadectomy. Instead, these differences are attributable to lower male expression of the epigenetic regulator Kdm6a (UTX), a X chromosome gene which escapes X inactivation in both human and mouse NK cells. NK cell-specific UTX deletion phenocopied multiple features of male NK cells, which include increased numbers and reduced IFN-γ production. Moreover, NK cell UTX is critical for optimal anti-viral immunity, since mice with NK cell UTX deficiency show increased lethality to mouse cytomegalovirus (MCMV) challenge. Integrative ATAC-seq and RNA-seq analysis revealed a critical role for UTX in maintaining open chromatin accessibility and gene expression of Ifng, Csf2, Thy1, and other gene loci important in NK cell homeostasis and effector function. Taken together, these data implicate UTX as a critical molecular determinant of NK cell sex differences and suggest enhancing UTX function may be a new strategy to boost endogenous NK cell anti-viral responses.