The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity
Yuichiro Itoh, … , Arthur P. Arnold, Rhonda R. Voskuhl
Yuichiro Itoh, … , Arthur P. Arnold, Rhonda R. Voskuhl
Published August 12, 2019
Citation Information: J Clin Invest. 2019;129(9):3852-3863. https://doi.org/10.1172/JCI126250.
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Research Article Autoimmunity Genetics

The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

Abstract

Multiple sclerosis (MS) is a putative T cell–mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4+ T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model showed higher expression in XX compared with XY. Deletion of Kdm6a 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, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

Authors

Yuichiro Itoh, Lisa C. Golden, Noriko Itoh, Macy Akiyo Matsukawa, Emily Ren, Vincent Tse, Arthur P. Arnold, Rhonda R. Voskuhl

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Figure 3

Differences in Th1/Th2 activation and neuroinflammation signaling pathways in CD4 Kdm6a KO mice.

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Differences in Th1/Th2 activation and neuroinflammation signaling pathwa...
(A) Scatterplot shows upregulated (red) and downregulated (blue) genes in CD4+ T cells in cKO as compared with WT. Differentially expressed genes were identified with edgeR (FDR < 0.1, logFC > 1 or logFC < –1, logCPM > 1). Other genes filtered out with this threshold are shown as gray dots. (B) The expression difference of 5 genes was validated with RT- PCR using biological replicates of 3 WT and 3 cKO: increased in cKO (Klra7: P = 0.0018, Ccl5: P = 0.0012), decreased in cKO (P2rx7: P = 0.0017, Tlr1: P = 0.0017, Cxcl10: P = 0.0204, t tests). In box-and-whisker plots, thick lines inside boxes represent the median of the data. Lower and upper ends of boxes show quantiles (25% and 75%), and whiskers show minimum and maximum values. P values were determined by t test. (C and D) Top 10 canonical pathways for the differentially expressed genes between WT and cKO CD4+ T cells. Significantly expressed genes (FDR < 0.1, logCPM > 1) were classified into 2 groups, and canonical pathway analysis was performed for each: (C) upregulated genes (logFC > 1) and (D) downregulated genes (logFC < –1), each in cKO as compared with WT. Genes within the top upregulated pathways in C (Th1 and Th2 activation pathway) and downregulated pathway in D (neuroinflammation signaling pathway) were visualized for their significance levels with volcano plots (E and F, respectively; pink dots represent Th1 and Th2 activation pathway genes, and green dots represent neuroinflammation signaling pathway genes). Gray circles represent all other genes not in these pathways, with the blue line as a threshold of significance (FDR = 0.1: any gene above this line considered significantly different). (G) Heatmaps for genes within the top canonical pathways: Th1 and Th2 activation pathway and neuroinflammation signaling pathway (red indicates upregulated, green represents downregulated).