The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease promoting in autoimmune disease

Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically 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, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility. Overall design: To determine the influence of differential Kdm6a expression in immune responses, we induced EAE in cKO mice (Kdm6a gene is conditionally knocked out in CD4 cells) and their WT littermate controls. On EAE day 17, lymph node cells were isolated and cultured with autoantigen (MOG35-55) before CD4+ T cell sorting. Whole transcriptome analysis for CD4+ T cells from WT and cKO EAE mice were performed using RNA-Seq.