Decidual NR2F2-Expressing CD4+ T Cells Promote TH2 Transcriptional Program During Early Pregnancy

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.

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

“…In the decidual microenvironment, CD4+ T cells exhibit an activated/memory CD25dim phenotype, whereas CD8+ T cells exhibit an effector/memory CD28-cell surface phenotype. The balance of the helper T (Th) 1 and Th2 cells changes trending towards an abundance of Th2 cells in the early stage is thought as a maker for successful pregnancy (75). The Treg cell population expresses intracellular fork-head box transcription factor (FOXP)-3 and activates i m m a t u r e D C s w h i c h i n t u r n p a r t i c i p a t e i n immunomodulatory and proangiogenic functions (76).…”

Recurrent implantation failure: A comprehensive summary from etiology to treatment

“…T cells constitute 5–20% of CD45 + decidual lymphocytes, which display different functions compared to peripheral blood T cells ( 55 ). Th2 cell dominance is essential for normal pregnancy ( 56 ). An imbalance of Th1/Th2 is associated with reproductive dysfunction.…”