Amsalem Hagai, Gaiger Anat, Mizrahi Sa'ar, Yagel Simcha, Rachmilewitz Jacob
Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
Int Immunol. 2008 Sep;20(9):1147-54. doi: 10.1093/intimm/dxn072. Epub 2008 Jul 14.
One of the most intriguing mechanisms of early pregnancy is the maternal immune tolerance toward her semi-allogeneic fetus, specifically in face of the accumulation of lymphocytes to high numbers at implantation sites. Here, we propose that a regulatory decidual lymphocyte (dL) population prevent the activation of reactive T cells and by that may maintain immune tolerance in the decidua. dLs were isolated from first trimester decidua and were then co-cultured with PBMC that were stimulated with anti-CD3 mAbs. Cytokine secretion to the media as well as the proliferative response were tested. The data demonstrate that dLs inhibit the production of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) and IL-5 but not CD25 expression, IL-2 production or proliferation in the responder PBMC. Suppression is mediated by a cell contact-dependent mechanism, was not restricted by the MHC and was not reversed by the addition of exogenous IL-2 although the inhibitory sub-population was identified as CD3+CD4+CD25+Foxp3+ natural regulatory T cells (Treg). Interestingly, suppression can also be overcome by the addition the endotoxin LPS, suggesting a mechanism for preterm labor triggered by chorioamnionitis. While these characteristics are in contrast to known peripheral CD4+CD25+ Treg activity, we identified these cells as the cellular subset responsible for the regulatory activity, suggesting that in decidua a functionally unique regulatory lymphocyte subset exist. These findings suggest the existence of a dynamic regulatory system in human decidua that is highly responsive to environmental factors.
早期妊娠最引人入胜的机制之一是母体对其半同种异体胎儿的免疫耐受，特别是在植入部位淋巴细胞大量积聚的情况下。在此，我们提出一种调节性蜕膜淋巴细胞（dL）群体可防止反应性T细胞的激活，从而可能维持蜕膜中的免疫耐受。从孕早期蜕膜中分离出dL，然后将其与用抗CD3单克隆抗体刺激的外周血单核细胞（PBMC）共培养。检测培养基中的细胞因子分泌以及增殖反应。数据表明，dL抑制应答性PBMC中γ干扰素、肿瘤坏死因子-α（TNF-α）和白细胞介素-5的产生，但不抑制CD25表达、白细胞介素-2产生或增殖。抑制作用由细胞接触依赖性机制介导，不受主要组织相容性复合体（MHC）限制，并且尽管抑制性亚群被鉴定为CD3+CD4+CD25+Foxp3+自然调节性T细胞（Treg），但添加外源性白细胞介素-2并不能逆转这种抑制作用。有趣的是，添加内毒素脂多糖（LPS）也可以克服这种抑制作用，这提示了绒毛膜羊膜炎引发早产的一种机制。虽然这些特征与已知的外周CD4+CD25+Treg活性相反，但我们将这些细胞鉴定为负责调节活性的细胞亚群，这表明在蜕膜中存在功能独特的调节性淋巴细胞亚群。这些发现提示人类蜕膜中存在一个对环境因素高度敏感的动态调节系统。
