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 5

T cell proliferation and cytokine production in Kdm6a cKO and WT mice.

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T cell proliferation and cytokine production in Kdm6a cKO and WT mice. (...
(A–E) Healthy female CD4+ T cells from WT (n = 5) and cKO (n = 5) mice were stained with CFSE and then cultured with anti-CD3/CD28 for 4 days, followed by flow cytometric analysis. (A) The proliferation index was similar between WT and cKO CD4+ T cells. (B) The division index of cKO CD4+ T cells was lower than that of WT. (C) There was a higher percentage of undivided CD4+ T cells in cKO than WT. (D-E) Representative CFSE histograms of viable CD4+ T cells in WT (D) and cKO (E). (F) Healthy female CD4+ T cells from WT (n = 5) and cKO (n = 5) were cultured with anti-CD3/CD28 antibodies for 36 hours. Analysis of supernatants showed a decrease in IL-2 and IL-17A, while IFN-γ was significantly increased in cKO compared with WT, with no difference in IL-5. (G) Female EAE lymphocytes were isolated from WT (n = 5) and cKO (n = 4) mice at EAE day 29 and cultured with autoantigen for 36 hours. Analysis of supernatants showed a significant decrease of IL-2, IL-17A, and IFN-γ, while IL-5 was significantly increased in cKO compared with WT. P values were calculated by unpaired, 2-tailed t test. Error bars represent SEM.