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 Article has an altmetric score of 69

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 4

A shift toward a naive phenotype in CD3+CD4+ T cells from Kdm6a cKO as compared with WT healthy mice.

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A shift toward a naive phenotype in CD3+CD4+ T cells from Kdm6a cKO as c...
Spleens were collected from healthy female WT and Kdm6a cKO mice for flow cytometry analysis of single-cell suspensions in 3 separate experiments (Exp1, red; Exp2, purple; Exp3, black). (A) There was no significant difference in the percentage of CD3+ cells. However, there was a decrease in CD3+CD4+ and an increase in CD3+CD8+ and CD3+NK1.1+ T cells in the cKO. (B) Within the CD3+CD4+ population, there was an increase in naive T cells (CD44loCD62Lhi), a decrease in memory T cells (CD44hiCD62Llo), and a decrease in CD44 MFI in the cKO. P values were calculated by unpaired 2-tailed t test. Error bars represent SD. (C) Representative dot plots show CD3+CD4+ naive and memory T cell populations in WT (left) and cKO (right). (D) cKO mice have more repressive H3K27me3 modifications on Cd44 compared with WT. ChIP-Seq data for H3K27me3 modification in mature CD4 single-positive thymocytes from WT and cKO were obtained from the GEO database (GSE70795; ref. 38). Without Kdm6a (cKO), the amount of H3K27me3 modification was increased around the transcription start site. (E) In healthy CD4+ T cells, RNA expression of Cd44 was downregulated in cKO (FDR = 0.009, edgeR), consistent with the increase of repressive histone marks, with less H3K27me3 histone demethylase activity in cKO. 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.