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）：成功的怀孕需要协调调节免疫系统的先天和适应性武器。蜕膜化的子宫内膜由母体白细胞，主要是子宫自然杀伤（NK）细胞，T细胞，巨噬细胞和树突状细胞组成。本提案的长期目标是了解这些蜕膜白细胞亚群之间的功能关系，并了解它们对妊娠成功和维持的贡献。半不变NKT（iNKT）细胞包含在蜕膜中积累的新的T细胞亚群。iNKT细胞识别最近证明在绒毛外滋养层上表达的CD 1d。我们的中心假设是，蜕膜iNKT细胞可以调节蜕膜NK细胞的功能，这种功能关系可能会影响妊娠结局。通过给予CD 1d配体α-半乳糖神经酰胺（aGalCer）刺激妊娠小鼠的iNKT细胞，可诱导小鼠妊娠丢失。我们建议通过阐明iNKT细胞激活介导小鼠妊娠丢失的机制来验证我们的假设。具体地，我们提出了一种模型，其中aGalCer刺激的iNKT细胞激活CD 40+抗原呈递细胞（APC）。活化的APC然后刺激蜕膜NK细胞，其最终以穿孔素依赖性方式介导妊娠丢失。为了测试该模型，我们提出了以下具体目标：（1）阐明iNKT细胞介导的妊娠丢失所需的iNKT衍生信号，（2）阐明iNKT细胞介导的妊娠丢失中涉及的CD 40+中间体的功能和表型，以及（3）阐明介导穿孔素依赖性妊娠丢失的细胞的作用和身份。这些目标的完成可能会提供深入了解蜕膜白细胞的功能性贡献的病理条件的怀孕。