Human Decidual Leukocytes and Their Placental Ligands

描述(申请人提供)：子宫中的胎儿带有父亲的抗原，应该被母体免疫系统作为异体移植排斥，这是彼得·梅达瓦50多年前描述的一个免疫学之谜。子宫蜕膜中的母体白细胞在耐受性中起着重要作用。它们与附着并侵入蜕膜的胎盘绒毛外滋养层细胞(EVT)相互作用。EVT表达一种功能未知的不同寻常的I类MHC蛋白，即只在孕妇和类人猿中发现的人类白细胞抗原-G二聚体。这项建议的目的是描述母体白细胞和胎儿EVT的特征，并研究它们之间的相互作用，这些相互作用必须有助于妊娠的各个方面，包括子宫螺旋动脉的重塑以增加流向发育中胎儿的血液，将胚泡(16细胞期胚胎)植入子宫，以及母胎耐受性。蜕膜自然杀伤细胞(蜕膜中约70%的白细胞在该项目的前5年中被描述为特征)通过几种方式促进母婴耐受。这一建议旨在描述蜕膜白细胞的其余主要部分，巨噬细胞(约占白细胞的20%)和T细胞(占白细胞的5%~20%)，以描述这些细胞之间发生的突触，并扩大我们对携带EVT的HLA-G二聚体与蜕膜白细胞相互作用的了解。微阵列分析将作为鉴定人蜕膜巨噬细胞的主要工具，以确定它们是否是M2调节巨噬细胞以及它们可能分泌哪些因子。它们可能在母胎耐受性和子宫重塑中发挥重要作用。包括调节性T细胞在内的蜕膜T细胞(占白细胞的5%-20%)的研究也将启动。侵袭蜕膜并与蜕膜白细胞混合的EVT最近被分离出来。它们将被进一步表征，并用于研究它们与蜕膜自然杀伤细胞和巨噬细胞的相互作用。我们已经证实，这些相互作用导致几种细胞因子的分泌，并假设参与母胎耐受和子宫重塑的其他蛋白质也会分泌。最后，将通过研究LIF对表达LIF受体的EVT的影响来研究LIF促进植入的机制。LIF基因敲除的雌性小鼠是不育的，因为受孕后形成的囊胚不能植入子宫。该项目与妇女的生殖失败直接相关，即反复自然流产(RSA)、因胚泡着床失败而导致的某些形式的不孕症、先兆子痫以及由于提供充足血液供应的血管重塑失败而导致的胎儿生长受限。

DESCRIPTION (provided by applicant): The fetus in utero bears paternal antigens and should be rejected as a foreign graft by the maternal immune system, an immunological enigma described by Peter Medawar more than 50 years ago. Maternal leukocytes that populate the uterine decidua certainly play an important role in tolerance. They interact with placental extravillous trophoblasts (EVT) that attach to and invade the decidua. EVT express an unusual Class I MHC protein of unknown function, the HLA-G dimer that is found only in pregnant women and apes. The goal of this proposal is to characterize both maternal leukocytes and fetal EVT and to study their interactions that must contribute to various aspects of pregnancy, including remodeling of the uterine spiral arteries to increase blood flow to the developing fetus, implantation of the blastocyst (16 cell stage embryo) into the uterus and maternal- fetal tolerance. Decidual natural killer cells (~70% of leukocytes in the decidua that were characterized during the first 5 years of this project) contribute to maternal-fetal tolerance by several means. This proposal seeks to characterize the remaining major sets of decidual leukocytes, the macrophages (~20% of the leukocytes) and T cells (5-20%), to describe synapses that occur between these cells, and to expand our knowledge of the interaction of HLA-G dimer bearing EVT with decidual leukocytes. Microarray analysis will be used as a principal tool in characterizing human decidual macrophages in order to establish whether they are M2 regulatory macrophages and what factors they may secrete. They may have an important role in maternal-fetal tolerance and in uterine remodeling. Studies of decidual T cells (5-20% of the leukocytes) that include regulatory T cells will also be initiated. The EVT that invade the decidua and intermingle with the decidual leukocytes have been recently isolated. They will be characterized further and used to study their interaction with decidual natural killer cells and macrophages. We have already established that these interactions lead to the secretion of several cytokines and hypothesize that other proteins involved in maternal- fetal tolerance and in uterine remodeling are also secreted. Finally, the mechanism by which LIF contributes to implantation will be examined by studying its effects on EVT that express the LIF receptor. LIF knockout female mice are infertile because the blastocyst formed after conception cannot implant into the uterus. This project is directly related to reproductive failure in women, i.e. recurrent spontaneous abortion (RSA), some forms of infertility due to failure of implantation of the blastocyst, preeclampsia and fetal growth restriction due to the failure of vascular remodeling that provides an adequate blood supply.