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 1

Differentially expressed X chromosome genes in mouse CD4+ T cells.

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Differentially expressed X chromosome genes in mouse CD4+ T cells. (A) U...
(A) Using the high-throughput sequencing approach, sexually biased X chromosome genes in CD4+ T cells were determined for C57BL/6J naive CD4+ T cells from spleen (GSE94671; 3 males and 3 females). Yellow dots within the bar representing the X chromosome indicate genes with higher expression in females than in males (threshold for significance was FDR < 0.1). Kdm6a showed increased expression in CD4+ T cells from females as compared with males. Xist and Tsix, which regulate X inactivation, and 4 predicted genes with unknown functions (Gm26992, Gm27733, Gm27927, and Gm27520) also showed increased expression in females. Shown below the bar representing the X chromosome are previously reported X escapees found in other tissues (black text) as well as X genes not thought to escape X inactivation, but involved in immunity (blue text) (58, 59). None had significantly different expression. (B–E) Expression of Kdm6a in (B) naive CD4+ T cells from C57BL/6J spleen (GSE94671; 3 males and 3 females); (C) stimulated CD4+ T cells from C57BL/6J lymph nodes (GSE121292; FCG: 6 XX and 6 XY‾); (D) stimulated CD4+ T cells from SJL lymph nodes (GSE121705; FCG: 6 XX and 5 XY‾); and (E) human naive CD4+ T cells from healthy control blood (GSE56033; 205 males and 294 females). In box-and-whisker plots, thick lines inside the boxes represent the median of the data. The lower and upper ends of boxes show quantiles (25% and 75%), and whiskers show the minimum and maximum values excluding outliers (circles). FDR was calculated using R package edgeR for A–D. For E, 1-way ANOVA was used.