Abstract
A unique immunotolerant microenvironment with Th2 bias in the decidua provides an essential security for successful pregnancy. The disorganized maternal-fetal immune tolerance contributes to more than 50% of unexplained recurrent spontaneous abortion (RSA). How the Th2 bias is developed at the maternal-fetal interface remains undefined. NR2F2, a member of steroid/thyroid nuclear receptor superfamily, is endowed with diverse importance in cell-fate specification, organogenesis, angiogenesis, and metabolism. Here, we showed that NR2F2 was absolutely highly expressed in decidual CD4+T(dCD4+T) cells, but not in peripheral circulating CD4+T cells during early pregnancy. Decidual NR2F2-expressing CD4+T cells dominantly produced Th2 cytokines. In unexplained RSA patients, NR2F2 expression in dCD4+T cells was significantly decreased, accompanied with disordered phenotype of dCD4+T cells. Furthermore, overexpression of NR2F2 promoted the Th2 differentiation of naive CD4+T cells. Immunoprecipitation experiment confirmed the binding relationship between GATA-3 and NR2F2, which implied GATA-3 may be an important interactive element involved in the immunoregulatory process of NR2F2. This study is the first to reveal a previously unappreciated role for NR2F2-mediated dCD4+T cells in maternal-fetal immune tolerance and maintenance of normal pregnancy, in the hope of providing a potential biomarker for prediction and prevention of clinical unexplained RSA.
Highlights
The fantastic phenomenon is worthy to be explored that semi-allogeneic fetus can avoid the attack or rejection from the maternal immune system during successful pregnancy [1]
Decidual tissue samples were obtained from women with unexplained recurrent spontaneous abortion (RSA) that occurred during the first trimester of pregnancy (The diagnostic criteria of RSA utilized in this study is patients undergoing spontaneous abortion who had a history of two or more consecutive spontaneous abortions before 12 weeks gestation without known causes, and excluding those resulting from endocrine, anatomic, genetic abnormalities, infection, etc. gestational age 6–12 weeks, n= 20)
DCD4+ T cells derived from RSA and normal pregnancies (NP) were compared via mRNA-seq
Summary
The fantastic phenomenon is worthy to be explored that semi-allogeneic fetus can avoid the attack or rejection from the maternal immune system during successful pregnancy [1]. Complicated immunoregulation is required to accurately create an immune-tolerant microenvironment at the fetal-maternal interface and maintain the process of pregnancy [2, 3]. Once the maternal-fetal immune tolerance is disrupted, various pregnancy-related complications may be elicited, such as NR2F2 Induces Th2 in Pregnancy recurrent spontaneous abortion (RSA), pre-eclampsia, and fetal intrauterine growth restriction [4, 5]. Spontaneous abortion is the most common complication of gestation, occurring in about 15% of human pregnancies. Accumulating evidences have proved CD4+T cells are crucial in inducing and maintaining maternal-fetal tolerance. Some cohort studies demonstrate spontaneous abortion is correlated with the decreased proportions of decidual regulatory CD4+T cells (Tregs). Increased decidual CD4+T help (Th) 1/Th2 ratio and elevated Th17 proportions are detected in RSA. Whether a representative immune marker or transcriptional regulatory molecule exists in decidual CD4+T cells (dCD4+ T) to explain the specific decidual phenotype remains unknown
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