X-chromosome inactivation maintenance is perturbed in T cells from lupus mouse models and human lupus patients

Abstract

Abstract Sex differences exist with immune responses, yet females are more susceptible to autoimmune and inflammatory disorders. One important biological factor underlying this sex bias is the X-chromosome, which is enriched for immunity-related genes. Female mammals use X-Chromosome Inactivation (XCI) to equalize gene expression between the sexes, which generates a transcriptionally silent inactive X-chromosome enriched with heterochromatic modifications and the long noncoding RNA Xist. We have discovered that mature naïve T cells are missing Xist RNA and heterochromatin marks on the inactive X (Xi), and these marks return to most cells with in vitro stimulation. During T cell development in the thymus, Xist RNA is not localized to the Xi and heterochromatin marks are progressively lost. Xist RNA returns to the Xi in mature T cell subsets between days 2 and 3 of in vitro activation. During lupus disease progression in the female-biased mouse model NZB/W F1, Xist RNA signals aberrantly appear in naïve T cells and Xist RNA becomes mis-localized from the Xi in activated T cells. These abnormal XIST RNA localization patterns are also observed in activated T cells from pediatric lupus patients in disease remission. Using next-generation sequencing, we found significant overexpression of X-linked genes across the X in female SLE T cells compared to healthy females. We propose that the dynamic mechanism of XCI maintenance female lymphocytes predisposes the Xi to become partially reactivated and to overexpress immunity-related genes. Our work provides the first mechanistic evidence for the female-specific enhanced immune responses and increased susceptibility for autoimmunity.