T cell activation and the breakdown of maternal-fetal tolerance in preterm labor

 描述(由申请人提供)：早产(定义为怀孕37周前分娩)是发达国家新生儿发病率和死亡率的最重要原因，而且其发病率还在继续上升。目前的治疗方法疗效有限，因为导致分娩的基本机制--无论是足月分娩还是早产--尚不清楚。由于成功怀孕取决于母亲和胎儿之间的多层耐受性，妊娠并发症可能涉及到这种机制的崩溃。我们建议检验这一新的假设，即妊娠期间感染或炎症导致针对胎儿或胎盘抗原的母体T细胞的激活，以及针对母体抗原的胎儿T细胞的激活，最终导致排斥和早产。我们将使用小鼠模型和患者样本来验证这一假设。在我们的小鼠模型中，我们之前已经证明了胎儿干预(一种无菌炎症模型)激活了母体T细胞，这些T细胞是 这种激活可能导致同种异体胎儿选择性死亡。这一发现与其他关于在怀孕小鼠感染李斯特菌期间T细胞激活和胎儿丧失的报道是一致的。我们现在将使用一种新型的Nur77-Foxp3双报告小鼠来描述这些发现的细胞机制，该小鼠跟踪T细胞受体在效应器和调节性T细胞中的参与。在我们的患者样本中，我们开发了可靠的分析方法来计数同种异体T细胞，以检查它们对临床早产(PTL)的可能贡献。我们有一个令人惊讶的发现，在妊娠期间，母血中T细胞的增殖受到抑制，但在继发于感染的PTL患者中，胎儿(脐带血)T细胞被激活。我们建议对继发于感染或胎儿干预的PTL患者的母体组织层中与胎盘(蜕膜)接触的母体T细胞是否在PTL期间被激活，以及导致胎儿T细胞早期激活的机制进行研究。后者通常在我们机构用于治疗胎儿先天畸形，但导致PTL的发生率显着增加。在目标1中，我们将在两种妊娠并发症的背景下分析小鼠的效应器和调节性T细胞激活：胎儿干预和宫内感染。在目标2中，我们将使用一种新的功能检测方法来检测PTL患者对胎儿和胎盘抗原的母体免疫反应，以追踪同种异体特异性T细胞，并探索在炎症过程中可能受到干扰的耐受机制的变化。在目标3中，我们将检测PTL患者的胎儿T细胞反应，以了解该人群中T细胞加速成熟的机制。我们的短期目标是了解母体和胎儿T细胞在PTL发病机制中的可能作用。我们的长期目标是了解导致足月和早产的机制，深入了解胎儿和新生儿T细胞的发育及其对新生儿健康的影响，并最终开发有针对性的疗法来阻止PTL风险患者的T细胞激活。

 DESCRIPTION (provided by applicant): Preterm birth (defined as delivery before 37 weeks of gestation) is the most important cause of neonatal morbidity and mortality in the developed world and its incidence continues to rise. Current treatments have limited efficacy because the fundamental mechanisms leading to labor-whether term or preterm-are not known. Since successful pregnancy depends on multi-layered tolerance between the mother and the fetus, pregnancy complications may involve a breakdown in such mechanisms. We propose to examine the novel hypothesis that infection or inflammation during pregnancy results in the activation of maternal T cells specific for fetal or placental antigens, and of fetal T cells speciic for maternal antigens, ultimately resulting in rejection and preterm delivery. We will use mouse models and patient samples to test this hypothesis. In our mouse model, we have previously shown that fetal intervention (a model of sterile inflammation) activates maternal T cells that are specific for fetal antigens and that this activation can cause selective demise of allogeneic fetuses. This finding is consistent with other reports of T cell activation and fetal loss during Listeria infection in pregnant mice. We will now delineate the cellular mechanisms of these findings using a novel Nur77-Foxp3 double reporter mouse that tracks T cell receptor engagement in both effector and regulatory T cells. In our patient samples, we have developed robust assays to enumerate allospecific T cells to examine their possible contribution to clinical preterm labor (PTL). We made the surprising discovery that T cell proliferation in maternal blood is blunted during pregnancy but that fetal (cord blood) T cells are activated in patients with PTL secondary to infection. We propose to examine whether maternal T cells in the maternal tissue layer in contact with the placenta (the decidua) become activated during PTL, and the mechanisms leading to early activation of fetal T cells, in patients with PTL secondary to infection or fetal intervention. The latter is commonly performed at our institution to treat fetuss with congenital anomalies but results in a significantly increased rate of PTL. In Aim 1, we will analyze effector and regulatory T cell activation in mice in the context of two pregnancy complications: fetal intervention and intrauterine infection. In Aim 2, we will examine maternal immune responses against fetal and placental antigens in patients with PTL using a novel functional assay to track allospecific T cells and explore changes in tolerance mechanisms that may be perturbed during inflammation. In Aim 3, we will examine fetal T cell responses in patients with PTL to understand the mechanisms of accelerated T cell maturation in this population. Our short-term goal is to understand the possible contribution of maternal and fetal T cells to the pathogenesis of PTL. Our long-term goals are to understand mechanisms leading to term and preterm labor, to gain insights into fetal and neonatal T cell development and its consequences for neonatal health, and, ultimately, to develop targeted therapies to impede T cell activation in patients at risk for PTL.