Engler Jan Broder, Kursawe Nina, Solano María Emilia, Patas Kostas, Wehrmann Sabine, Heckmann Nina, Lühder Fred, Reichardt Holger M, Arck Petra Clara, Gold Stefan M, Friese Manuel A
Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany.
Experimentelle Feto-Maternale Medizin, Klinik für Geburtshilfe und Pränatalmedizin, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany.
Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E181-E190. doi: 10.1073/pnas.1617115114. Epub 2017 Jan 3.
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.
怀孕是免疫耐受最强的诱导因素之一。包括多发性硬化症（MS）在内的许多自身免疫性疾病的疾病活动在孕期会暂时受到抑制，但对于其潜在的分子机制却知之甚少。在此，我们研究了生殖过程中传统T细胞和调节性T细胞（Tregs）的内分泌调节。在体外，我们发现妊娠激素孕酮通过与T细胞中的糖皮质激素受体（GR）随意结合，有力地增加了Tregs的频率。在体内，患有实验性自身免疫性脑脊髓炎（EAE，MS的动物模型）的怀孕动物中，T细胞特异性GR缺失导致Tregs增加减少以及妊娠诱导保护的选择性丧失，而生殖成功不受影响。我们的数据表明，类固醇激素可通过T细胞中GR的不同参与来改变免疫平衡，使之有利于Tregs。这一新定义的机制赋予孕期免受自身免疫性疾病侵害的保护作用，并代表了未来治疗的一个潜在靶点。
