The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity

Abstract

This sex difference of KDM6A gene expression was confirmed in human naive CD4 + T cells (Figure 1E). That other genes thought to escape X inactivation do not appear when comparing female versus male CD4 + T cell data sets may be due to a variety of factors, such as the tissue type, cell type, or hormonal status (28). We then used the FCG mouse model (20, 21), which allows comparison of XX and XY‾ mice of the same gonadal sex (Y‾ denotes lack of the testis-determining Sry gene on the Y chromosome). In addition, XX and XY‾ gonadal females were ovariectomized to remove activational effects of ovarian hormones. In autoantigen-stimulated CD4 + T cells from C57BL/6J and SJL mice, there was higher expression of Kdm6a and Kdm5c in XX compared with XY‾ mice (Figure 1, C and D, and Supplemental Figure 1, B and C). In contrast, other genes thought to escape X inactivation, namely, Ddx3x, Eif2s3x, Uba1, and Usp9x, were not differentially expressed between XX and XY‾ CD4 + T cells (Supplemental Figure 1, B and C). cKO mice are protected from EAE. Since Kdm6a was the most differentially expressed X escapee, we next investigated to determine whether Kdm6a expression in CD4 + T cells influences autoimmune disease. We crossed mice containing homozygous floxed Kdm6a alleles with mice expressing Cre under the CD4 promoter to produce a conditional KO of Kdm6a only in CD4 + T cells (cKO). Deletion of Kdm6a in CD4 + T cells was confirmed with genomic PCR (Figure 2A). As expected, expression of Kdm6a was decreased in cKO compared with WT in the CD4 + T cells from EAE mice that were stimulated with autoantigen (Figure 2B, FDR = 0.07). To examine the functional significance of Kdm6a expression in CD4 + T cells on disease, active EAE was induced in female cKO and WT (littermate controls; CD4-Cre negative) mice (Figure 2C). EAE clinical scores of cKO mice were lower than those in WT mice (P < 0.0001), demonstrating that deletion of Kdm6a in CD4 + T cells was protective. This protective effect of Kdm6a deletion in CD4 + T cells was further confirmed with 3 additional EAE experiments, including 1 experiment in males (Table 1). Together, these data show that the presence of Kdm6a in CD4 + T cells is disease promoting in the classic CD4 + T cellmediated autoimmune disease EAE. Consistent with an amelioration of clinical EAE scores, immunohistochemistry of spinal cord white matter showed a reduction of CD3 + T lymphocytes and Iba1 + globoid macrophages in cKO compared with WT mice (Figure 2, D and E). Assessment of neurodegeneration in spinal cord white matter showed reduction of βAPP + injured axons and an increase in

Mechanisms of sex hormones in autoimmunity: focus on EAE

“…1). One such transcript is KDM6a where the animals deficient for this gene were found resistant for the development of EAE [61]. Other potential candidates include Forkhead box P3 (FoxP3) and Toll like receptor (TLR) 7 [62].…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…This gene codes for a histone demethylase that escapes X inactivation and its deletion in CD4+ T cells protects mice from EAE. Therefore, the higher expression of Kdm6a in females may contribute to their higher susceptibility for multiple sclerosis (Itoh et al, 2019).…”

“…The studies with the four core genotypes mouse model also suggest that sex differences in the immune system that are determined by sex chromosome complement may influence the manifestation of sex differences in brain pathology. Thus, in addition to the mentioned effects of sex differences in the expression of Kdm6a in CD4+ T cells in the susceptibility to EAE (Itoh et al, 2019), increased levels of proinflammatory cytokines may contribute to the higher brain infarct size and the higher microglia activation observed in male and female XX mice, compared to male and female XY mice, after middle cerebral artery occlusion (McCullough et al, 2016).…”

Significance of KDM6A Mutation in Bladder Cancer Immune Escape

“…KDM6A de ciency has been suggested to activate pathways of chemokines and cytokines, increase M2 macrophage polarization, increase cancer stem cell abundance, and act synergistically with p53 haploinsu ciency [22]. Given the key function of KDM6A in regulating CD4 + T cells, [23] concluded that KDM6A likely regulates multiple immune response genes in autoimmune disease susceptibility.…”