Sex- and species-specific CD99 expression of T cells and its implications in multiple sclerosis

Abstract

Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as MS. MS manifests in more than twice as many women, making sex one of the most important risk factors. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen using the GTEx project dataset to identify differentially expressed genes between women and men. We identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated. Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Hormones were ruled out as the cause by in vitro assays and ex vivo analysis of trans men samples. In CSF, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, female and male mice had similar CD99 expression and Cd99-deficient mice showed equal susceptibility to EAE compared to WTs. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction. Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.