Decidual T Cells in Immune-mediated Pregnancy Loss

 描述（由申请方提供）：妊娠子宫粘膜，称为蜕膜，在人类妊娠早期含有约15-30%的白细胞。最近的研究已经在人类和小鼠蜕膜中检测到自然杀伤T细胞。小鼠围着床期子宫含有大量的自然杀伤T细胞，但它们在妊娠中的功能尚不清楚。已知自然杀伤T细胞与脂质抗原反应，所述脂质抗原结合至称为CD 1d的非经典MHC I类脂质抗原呈递分子。在初步工作中，我们已经确定了T细胞与磷脂（PL）抗原在蜕膜，淋巴器官的小鼠以及在外周血中的人。这些新的PL反应性T细胞（PL-T）是相对丰富的蜕膜相比，在小鼠的淋巴器官和分泌细胞因子后，免疫与PL抗原在体内。PL-T细胞受CD 1d的限制。这种PL-T细胞在狼疮小鼠的蜕膜中比在健康品系中相对更多。本R21探索性提案的目标是了解PL-T细胞在免疫介导的妊娠丢失中的作用。在我们新观察的指导下，我们假设狼疮小鼠的PL-T细胞发生了改变;这种改变的PL-T细胞诱导妊娠丢失。在目的1中，我们将确定PL-T细胞对狼疮和抗磷脂综合征小鼠妊娠结局的作用。在目标2中，我们将开始翻译动物的发现。具体来说，我们将确定PL-T细胞是否存在于 人的蜕膜，以及来自狼疮/抗磷脂综合征患者的外周血和蜕膜PL-T细胞与来自正常孕妇的PL-T细胞相比是否显示出促炎细胞因子产生增加的活化表型。希望这项研究将促进我们对胎儿健康中蜕膜免疫细胞的理解，并阐明狼疮和自身免疫性疾病中免疫介导的妊娠丢失的新发病机制。

 DESCRIPTION (provided by applicant): The pregnant uterine mucosa, called decidua, contains ~15-30% of leukocytes in early pregnancy in humans. Recent studies have detected natural killer T cells in human and mouse decidua. The murine peri-implantation uterus contains an expanded population of natural killer T cells, but their function in pregnancy remains unclear. Natural killer T cells are known to react with lipid antigens bound to a non-classical MHC class I-like lipid antigen presenting molecule called CD1d. In preliminary work, we have identified T cells that react with phospholipid (PL) antigens in the decidua, and lymphoid organs of mice as well as in peripheral blood of humans. These novel PL-reactive T cells (PL-T) are relatively abundant in the decidua compared to lymphoid organs in mice and secrete cytokines upon immunization with PL antigens in vivo. The PL-T cells are restricted by CD1d. Such PL-T cells are relatively more in the decidua of lupus mice than in healthy strains. The goal of this R21 Exploratory proposal is to understand the role of PL-T cells in immune-mediated pregnancy loss. Guided by our novel observations, we hypothesize that PL-T cells are altered in lupus mice; such altered PL-T cells induce pregnancy loss. In Aim 1, we will determine the role of PL-T cells on pregnancy outcome in mice with lupus and anti-phospholipid syndrome. In Aim 2, we will begin to translate animal findings. Specifically, we will determine if PL-T cells exist in the decidua of humans, and whether peripheral blood and decidual PL-T cells from patients with lupus/anti-phospholipid syndrome display an activated phenotype with increased production of pro-inflammatory cytokines compared to PL-T cells from normal pregnant women. It is hoped that the study will advance our understanding of decidual immune cells in fetal health and elucidate a novel pathogenetic mechanism of immune-mediated pregnancy loss in lupus and autoimmune diseases.