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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE185065 | GEO | 2023/02/27

REPOSITORIES: GEO

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

Project description: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.

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Histone H3K27 demethylase negatively controls the memory formation of Ag-stimulated CD8+ T cells

Project description:Although the methylation status of histone H3K27 plays a critical role in CD4+ T cell differentiation and its function, the role of Utx, histone H3K27 demethylase, in the CD8+ T cell-dependent immune response remains unclear. We therefore generated T cell-specific Utx knockout (Utx KO) mice to determine the role of Utx in CD8+ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells upon primary and secondary infections. There was no significant differences in the primary expansion of Ag-specific CD8+ T cells between WT and Utx KO mice. However, Utx deficiency resulted in an increased secondary expansion of Ag-specific CD8+ T cells. Adoptive transferred Utx KO CD8+ T cells resulted in increased numbers of CD127hi KLRG1lo memory precursors in the primary expansion and larger numbers of memory cells. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8+ T cells upon primary infection. We confirmed that the tri-methylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8+ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, while Utx-inhibitor GSK-J4 enhanced the memory formation and increased the secondary expansion in WT CD8+ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells by epigenetically regulating the expression of genes, including Prdm1. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8+ T cells upon infection

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