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

Gonzalo Fernandez Lahore, Michael Förster, Martina Johannesson, Pierre Sabatier, Erik Lönnblom, Mike Aoun, Yibo He, Kutty Selva Nandakumar, Roman A. Zubarev and Rikard Holmdahl ()
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Gonzalo Fernandez Lahore: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Michael Förster: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Martina Johannesson: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Pierre Sabatier: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute
Erik Lönnblom: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Mike Aoun: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Yibo He: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Kutty Selva Nandakumar: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute
Roman A. Zubarev: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute
Rikard Holmdahl: Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25828-5

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