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 2

Deletion of Kdm6a in CD4+ T cells protects mice from EAE.

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Deletion of Kdm6a in CD4+ T cells protects mice from EAE. (A) Genomic PC...
(A) Genomic PCR for isolated CD4+ T cells from EAE mice showed successful deletion of Kdm6a in cKO mice homozygous for the KO allele. (B) In cKO mice, RNA expression of Kdm6a was downregulated in CD4+ T cells. RNA expression levels of Kdm6a were graphed with log2-transformed TPM normalization. In box-and-whisker plot, 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. FDR was calculated using edgeR. (C) cKO mice showed decreased EAE severity scores compared with WT littermates. n = 4 WT; n = 5 cKO. P < 0.0001, repeated measures 1-way ANOVA. Additional EAE experiments are shown in Table 1. (D) Representative ×10 images of the ventral spinal cord of EAE in WT and cKO stained with antibodies for CD3 (green), Iba1 (red), βAPP (red), and NF200 (red) costained with DAPI (blue). Scale bars: 100 μm. (E) Dot plots show a decrease in cKO for CD3+ cell count (P = 0.03276), globoid Iba1+ cell count (P = 0.02593), and βAPP+ percentage area for axonal damage (P = 0.01207), and show an increase in cKO for NF200+ intact axonal count (P = 0.03276) in the white matter. n = 8 WT; n = 11 cKO. The height of columns represents mean, and error bars represent SEM. For each stain, P value was determined by Mann-Whitney U test.