Polymorphic estrogen receptor binding site causes CD2-dependent sex bias in the susceptibility to autoimmune diseases

Abstract

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors likely determines the sex discrepancy in the immune response, but conclusive evidence is lacking regarding the underlying molecular mechanisms. Using forward genetics, we positionally identified a polymorphic estrogen receptor binding site that regulates CD2 expression, leading to female-specific differences in mouse models of T cell-dependent autoimmunity. Female mice with reduced CD2 levels displayed diminished expansion of autoreactive T cells. Mechanistically, CD2 affected T cell activation by inhibiting LAG-3 expression. Our findings explain the sexual dimorphism in human autoimmunity, as CD2 associated with rheumatoid arthritis and its regulation through 17-β-estradiol was conserved in human T cells. Hormonal regulation of CD2 has implications for CD2-targeted therapy. Indeed, anti-CD2 treatment was more potent in female mice. In conclusion, our results demonstrate the relevance of sex-genotype interactions and provide strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.