Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity

Abstract

Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4⁺ T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.

Keywords: IFNγ; IL-17; Jarid1c; Th17; experimental autoimmune encephalomyelitis; four core genotypes; multiple sclerosis; non-obese diabetic; progressive multiple sclerosis; sex chromosome complement.