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Low CD4CD8T-cell ratios occur in conditions associated with reduced immune resilience, including older age and HIV infection. Effective antiretroviral therapy increases CD4CD8T-cell ratios, but often not to preinfection levels. The reasons for this deficit remain unclear. As cytomegalovirus (CMV) infection exacerbates falling CD4CD8T-cell ratios and immune senescence in the old elderly population, we investigated whether CMV infection is associated with refractory inversion of CD4CD8T-cell ratios and increased phenotypic evidence of immune senescence in HIV infection.

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, Jarid1cexpression is downregulated in CD4+T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.