CD1D-Restricted T cells and Pregnancy Loss

CD1D 限制性 T 细胞与流产

• 批准号: 7570046
• 负责人: JONATHAN E BOYSON
• 金额: $ 37.28万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570046
• 关键词: Antigen-Presenting Cells; Binding; CD40 Antigens; CD40 Ligand; Cell physiology; Cells; Data; Decidua; Decidual Cell Reactions; Dendritic Cells; Dependence; Endometrium; Etiology; Frequencies; Galactosylceramides; Glycosphingolipids; Goals; Histocompatibility Antigens Class I; Human; Immune; Immune system; Inflammatory; Leukocytes; Ligands; MHC Class I Genes; Maternal-Fetal Exchange; Mediating; Modeling; Mus; Natural Killer Cells; Pathway interactions; Peptides; Phenotype; Population; Pre-Eclampsia; Pregnancy; Pregnancy Maintenance; Pregnancy Outcome; Pregnancy loss; Preparation; Production; Regulation; Research Personnel; Role; Signal Transduction; Staging; Surface; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFRSF5 gene; TNFSF5 gene; Testing; Upper arm; cytokine; insight; macrophage; novel; perforin; pregnant; programs; success; trophoblast

DESCRIPTION (provided by applicant): Successful pregnancy requires the coordinate regulation of the innate and adaptive arms of the immune system. The decidualized endometrium is populated by maternal leukocytes, primarily uterine natural killer (NK) cells, T cells, macrophages, and dendritic cells. The long-term goal of this proposal is to understand the functional relationships among these decidual leukocyte cell subsets and to understand their contribution to the success and maintenance of pregnancy. Semi-invariant NKT (iNKT) cells comprise a novel T cell subset that accumulates in the decidua. iNKT cells recognize CD1d which was recently demonstrated to be expressed on extravillous trophoblast. Our central hypothesis is that decidual iNKT cells can modulate decidual NK cell function, and that this functional relationship may influence pregnancy outcome. Stimulation of iNKT cells in pregnant mice, through administration of the CD1d ligand a-galactosylceramide (aGalCer), induces pregnancy loss in mice. We propose to test our hypothesis by elucidating the mechanism through which iNKT cell activation mediates pregnancy loss in the mouse. Specifically, we propose a model in which aGalCer-stimulated iNKT cells activate CD40+ antigen-presenting cells (APCs). Activated APCs then stimulate decidual NK cells, which ultimately mediate pregnancy loss in a perforin-dependent manner. To test this model we propose the following Specific Aims: (1) to elucidate the iNKT-derived signals required for iNKT cell-mediated pregnancy loss, (2) to elucidate the function and phenotype of the CD40+ intermediate involved in iNKT cell-mediated pregnancy loss, and (3) to elucidate the role and the identity of the cell(s) mediating perforin-dependent pregnancy loss. Completion of these aims may offer insight into the functional contributions of decidual leukocytes to pathological conditions of pregnancy.

描述（由申请人提供）：成功的怀孕需要对免疫系统先天和适应性臂的坐标调节。骨化性子宫内膜由母体白细胞填充，主要是子宫天然杀伤（NK）细胞，T细胞，巨噬细胞和树突状细胞。该提案的长期目标是了解这些决定性白细胞细胞子集之间的功能关系，并了解它们对妊娠成功和维持的贡献。半不变的NKT（INKT）细胞组成了一个新型的T细胞子集，该细胞积累了在DECIDUA中积累。 Inkt细胞识别CD1D最近被证明是在跨滋养细胞上表达的。我们的中心假设是，decidual Inkt细胞可以调节deciDual NK细胞功能，并且这种功能关系可能会影响妊娠结局。通过给予CD1D配体A-半乳糖基酰胺（Agalcer）刺激iNKT细胞在小鼠中诱导妊娠丧失。我们建议通过阐明Inkt细胞激活介导小鼠妊娠丧失的机制来检验假设。具体而言，我们提出了一个模型，其中agalcer刺激的Inkt细胞激活CD40+抗原呈递细胞（APC）。然后，激活的APC刺激了deciantal NK细胞，该细胞最终以穿孔蛋白依赖性方式介导妊娠丧失。要测试该模型，我们提出以下特定目的：（1）阐明Inkt细胞介导的妊娠损失所需的INKT衍生信号，（2）阐明与Inkt细胞介导的妊娠有关的CD40+中间体的功能和表型损失，（3）阐明细胞的作用和身份，介导穿孔蛋白依赖性妊娠丧失。这些目标的完成可能会深入了解判决白细胞对怀孕病理状况的功能贡献。