Identifying the factors driving disease disparities between males and females with multiple sclerosis (MS) holds great promise for deciphering immunopathogenic disease mechanisms. In this issue of JCI, Itoh et al. explore the basis for sexual dimorphism in autoimmunity, specifically in MS. Using the experimental autoimmune encephalomyelitis (EAE) model of MS, which recapitulates CD4+ T cell-dependent disease, the authors examined the contribution of Kdm6a, a histone demethylase gene known to escape X inactivation. Conditional knockout in CD4+ T cells revealed Kdm6a involvement with a collection of immunologic processes having the potential to skew immunity toward inflammatory responses. This study concisely shows the value of X chromosome gene expression in T cell regulation of autoimmunity and the relevance of Kdm6a in the pathogenesis of EAE as a model of MS.