CD1D-Restricted T cells and Pregnancy Loss

描述（由申请人提供）：成功妊娠需要免疫系统先天臂和适应臂的协调调节。脱个体子宫内膜由母体白细胞、主要是子宫自然杀伤细胞（NK）细胞、T细胞、巨噬细胞和树突状细胞组成。这项建议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）细胞包括在蜕膜中积累的一种新的T细胞亚群。iNKT细胞识别CD1d，最近证实CD1d在细胞外滋养细胞上表达。我们的中心假设是，iNKT细胞可以调节NK细胞的功能，这种功能关系可能影响妊娠结局。通过给药CD1d配体a-半乳糖神经酰胺（aGalCer）刺激怀孕小鼠的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。具体来说，我们提出了一个agalcer刺激的iNKT细胞激活CD40+抗原呈递细胞（APCs）的模型。活化的apc然后刺激蜕膜NK细胞，最终以穿孔依赖的方式介导妊娠丢失。为了验证这一模型，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所涉及的CD40+中间体的功能和表型，以及(3)阐明介导穿孔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提供洞见的功能贡献的蜕膜白细胞对妊娠病理条件。

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.