Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases.
Animals
Arthritis, Rheumatoid
/ genetics
Autoimmune Diseases
/ genetics
Autoimmunity
/ genetics
Binding Sites
/ genetics
CD2 Antigens
/ genetics
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
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
received:
17
03
2021
accepted:
20
08
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34552089
doi: 10.1038/s41467-021-25828-5
pii: 10.1038/s41467-021-25828-5
pmc: PMC8458462
doi:
Substances chimiques
CD2 Antigens
0
Estradiol
4TI98Z838E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5565Informations de copyright
© 2021. The Author(s).
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