PT  - JOURNAL ARTICLE
AU  - Mandy I. Cheng
AU  - Luke Riggan
AU  - Joey H. Li
AU  - Rana Yakhshi Tafti
AU  - Scott Chin
AU  - Feiyang Ma
AU  - Matteo Pellegrini
AU  - Haley Hrncir
AU  - Arthur P. Arnold
AU  - Timothy E. O’Sullivan
AU  - Maureen A. Su
TI  - Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX
AID  - 10.1101/2022.04.21.489076
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.21.489076
4099  - http://biorxiv.org/content/early/2022/04/29/2022.04.21.489076.short
4100  - http://biorxiv.org/content/early/2022/04/29/2022.04.21.489076.full
AB  - Viral infection outcomes are sex-biased, with males generally more susceptible than females. Paradoxically, the numbers of anti-viral natural killer (NK) cells are increased in males compared to females. Using samples from mice and humans, we demonstrate that while numbers of male NK cells are increased compared to females, they display impaired production of the anti-viral cytokine IFN-γ. These sex differences were not due solely to divergent levels of gonadal hormones, since these differences persisted in gonadectomized mice. Instead, these differences can be attributed to lower male expression of X-linked Kdm6a (UTX), an epigenetic regulator which escapes X inactivation in female NK cells. NK cell-specific UTX deletion in females phenocopied multiple features of male NK cells, which include increased numbers and reduced IFN-γ production. Integrative ATAC-seq and RNA-seq analysis revealed a critical role for UTX in the regulation of chromatin accessibility and gene expression at loci important in NK cell homeostasis and effector function. Consequently, NK cell-intrinsic UTX levels are critical for optimal anti-viral immunity, since mice with NK cell-intrinsic UTX deficiency show increased lethality to mouse cytomegalovirus (MCMV) challenge. Taken together, these data implicate UTX as a critical molecular determinant of NK cell sex differences and suggest enhancing UTX function as a new strategy to boost endogenous NK cell anti-viral responses.Competing Interest StatementT.E.O. is a scientific advisor for Xyphos Inc., a company that has financial interest in human NK cell-based therapeutics.