Abstract
Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.
Highlights
We have set out to identify major genetic polymorphisms underlying the development of autoimmune arthritis, using animal models
In a genetic association study, we found a significant association between CD2 polymorphisms and RA
We find that E2-mediated regulation of Cd2 is a conserved mechanism that influences T cell activation in a sexspecific manner, contributing to the sexual dimorphism in autoimmune diseases
Summary
Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice These results demonstrate the relevance of sexgenotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity. Women generally mount a more vigorous immune response than men, and are more susceptible to most autoimmune diseases[1,2] These diseases have a strong but complex genetic component, and it has been difficult to identify the underlying polymorphisms[3,4,5]. We report the causative mechanism to be a single polymorphism in an oestrogen receptor binding site (ERBS) within Cia[21] This polymorphic ERBS orchestrates the expression of its surrounding genes in a sex-specific manner, including Cd2. We find oestrogen regulation of CD2 expression to be a conserved mechanism in humans likely contributing to the sexual dimorphism in T cell-mediated autoimmune diseases
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