FUNCTIONAL COOPERATION BETWEEN TROPHOBLAST HLA-G AND B7 FAMILY

摘要-项目11 背景淋巴细胞的刺激需要由抗原提供的两个协同信号的传递 呈递细胞第一个信号由人类白细胞抗原（HLA）提供，而第二个信号由人类白细胞抗原（HLA）提供。 由B7家族的共刺激分子的一个成员。然而，与经典的抗原呈递细胞不同， 滋养层细胞具有两类分子的独特组合。特别是滋养层细胞 组成型表达非经典HLA-G分子以及新发现的B7家族成员B7- H1。体外和体内研究表明，B7和HLA蛋白的表达可以抑制白细胞 激活并改变细胞因子分泌，这些蛋白质的异常表达可导致 如癌症和自身免疫性疾病。我们的初步数据显示， H1_A-G和B7-H1还抑制T细胞产生促炎细胞因子干扰素-γ，表明 滋养层细胞利用这些分子来保护胎儿半同种异体移植物。我们和其他人也 研究表明，与先兆子痫相关的氧和促炎细胞因子， 早产，改变滋养层相关B7-H1和HLA-G的表达。因此， 胎盘中异常的氧和/或细胞因子条件引起的滋养层HLA和B7的沉淀， 导致滋养层细胞抑制母体白细胞的能力降低或增强。 具体目标。滋养细胞表达HLA和B7家族特异性成员的研究 细胞中的这些分子是否在功能上合作向淋巴细胞传递信号， 与这些家族的古典成员相似的方式。项目II的具体目标是：1）确定 正常妊娠和病理妊娠中HLA-G和B7-H1成员的相对表达水平; 2） 确定滋养层细胞B7-H1的存在是否影响滋养层细胞HLA-G对母体 3）检测B7-H1是否影响表达HLA-G1的T淋巴细胞的抗原呈递活性。 滋养层细胞系在目的1中，组织和纯化的滋养层细胞来自正常，先兆子痫， 和早产将通过分子、组织学和流式细胞术技术进行检查， 确定这些蛋白质的平衡是否在受损妊娠中被抵消。在目标2中，我们将 进行功能测定以比较HLA和B7家族分子单独和组合的能力， 调节白细胞功能。最后，目的3旨在确定滋养层相关HLA-G是否 可以在母胎界面提供抗病毒保护。在这里，我们将测试HLA-G是否可以呈现 病毒肽对T细胞的作用，以及B7-H1的存在是否影响其这样做的能力。

ABSTRACT-PROJECT 11 Background. Stimulation of lymphocytes requires the delivery of two cooperating signals provided by antigen presenting cells. The first signal is provided by human leukocyte antigens (HLA), while the second is provided by a member of the B7 family of costimulatory molecules. Unlike classical antigen presenting cells, however, trophoblast cells possess a distinctive combination of both classes of molecules. Specifically, trophoblast cells constitutively express non-classical HLA-G molecules as well as the newly discovered B7 family member, B7- H1. In vitro and in vivo studies have shown that expression of the B7 and HLA proteins can inhibit leukocyte activation and alter cytokine secretion, and that aberrant expression of these proteins can contribute to conditions such as cancer and autoimmune disease. Our preliminary data show that trophoblast-associated Hl_A-G and B7-H1 also inhibits production of the proinflammatory cytokine interferon-y by T cells, suggesting that trophoblast cells use these molecules for protection of the fetal semiallograft. We and others have also demonstrated that oxygen and proinflammatory cytokines, which are associated with preeclampsia and preterm delivery, alter expression of trophoblast-associated B7-H1 and HLA-G. Thus, altered expression of trophoblast HLA and B7s precipitated by abnormal oxygen and/or cytokine conditions in the placenta could lead to the reduced or enhanced ability of trophoblast cells to inhibit maternal leukocytes. Specific goals. The findings of the expression of unique members of the HLA and B7 families by trophoblast cells raises the question of whether these molecules functionally cooperate to deliver signals to lymphocytes in a manner similar to classical members of these families. The Specific Aims of Project II are to 1) determine the relative levels of expression of members of HLA-G and B7-H1 in normal and pathologic pregnancies; 2) determine whether the presence of trophoblast B7-H1 influences the effects of trophoblast HLA-G on maternal T lymphocytes; 3) examine whether B7-H1 influences antigen presentation activity of HLA-G1-expressing trophoblast cell lines. In Aim 1, tissue and purified trophoblast cells from placentas of normal, preeclamptic, and preterm pregnancies will be examined by molecular, histological, and flow cytometric techniques to determine whether the balance of these proteins is offset in compromised pregnancies. In Aim 2, we will perform functional assays to compare the ability of HLA and B7 family molecules, alone and in combination, to regulate leukocyte function. Finally, Aim 3 is designed to determine whether trophoblast-associated HLA-G can provide anti-viral protection at the maternal-fetal interface. Here, we will test whether HLA-G can present viral peptides to T cells, and whether the presence of B7-H1 affects its ability to do so.