Significance Reproduction in placental mammals relies on potent control of the mother’s immune system to not attack the developing fetus. As a bystander effect, pregnancy also potently suppresses the activity of the autoimmune disease multiple sclerosis (MS). Here, we report that T cells are able to directly sense progesterone via their glucocorticoid receptor (GR), resulting in an enrichment of regulatory T cells (Tregs). By using an MS animal model, we found that the presence of the GR in T cells is essential to increase Tregs and confer the protective effect of pregnancy, but not for maintaining the pregnancy itself. Better understanding of this tolerogenic pathway might yield more specific therapeutic means to steer the immunological balance in transplantation, cancer, and autoimmunity.

Abstract Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell–specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.

Footnotes Author contributions: J.B.E., S.M.G., and M.A.F. designed research; J.B.E., N.K., M.E.S., K.P., S.W., and N.H. performed research; F.L., H.M.R., and P.C.A. contributed new reagents/analytic tools; J.B.E., N.K., P.C.A., and M.A.F. analyzed data; and J.B.E. and M.A.F. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

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