Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases

Nat Commun. 2021 Sep 22;12(1):5565. doi: 10.1038/s41467-021-25828-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • Binding Sites / genetics
  • CD2 Antigens / genetics*
  • CD2 Antigens / immunology
  • CD2 Antigens / metabolism
  • Disease Models, Animal
  • Estradiol / metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Lymphocyte Activation
  • Male
  • Mice
  • Polymorphism, Genetic
  • Sex Characteristics
  • T-Lymphocytes / immunology


  • CD2 Antigens
  • Estradiol