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The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease-promoting in autoimmune disease

ABSTRACT: Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

ORGANISM(S): Mus musculus

PROVIDER: GSE128615 | GEO | 2019/10/18

REPOSITORIES: GEO

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Project description:Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiome bacteria on humoral immune activation. Sham-operated and gonadectomized male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotypes. Ex vivo studies investigated the functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, in mitogenic B cell activation. We further evaluated whether gut microbiome communities, or their metabolites, differentially influence immune cell activation in a sex chromosome-dependent manner. Endogenous gut microbiomes were antibiotically depleted and reconstituted with select short-chain fatty acid (SCFA)-producing bacteria prior to HKSP immunization and immune responses assessed. XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria increased humoral responses in XX, but not XY, FCG mice. This XX-dependent enhancement appears to be independent of SCFA production in males, while female XX-dependent responses relied on SCFAs. FCG mice have been used to assess sex hormones and sex chromosome complements influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphisms.

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The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease-promoting in autoimmune disease

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