Dendritic cell behavior at the maternal/fetal interface

描述(申请人提供)：胎儿和胎盘如何在怀孕期间逃避排斥反应可能涉及母体蜕膜内的局部免疫调节，蜕膜是包裹着植入胚胎的专门基质组织。令人惊讶的是，尽管树突状细胞类型在监测外周组织中的外来抗原和控制随后的免疫反应方面至关重要，但对母体/胎儿界面上的树突状细胞几乎一无所知。在这里，我们使用TCR转基因T细胞过继转移和模型抗原转基因系统来测试胎儿和胎盘唯一表达的抗原是否确实是由子宫引流淋巴结内的树突状细胞递送的，以及T细胞反应是耐受性还是免疫性(目标1)。然后，我们将直接描述蜕膜树突状细胞的表型，并询问这些细胞是否在炎症和动态平衡条件下适当地成熟并从子宫中迁出(目标2)。第三，我们将确定树突状细胞在蜕膜和子宫肌层的差异性募集，并确定新招募的祖细胞的命运(目标3)。最后，我们将研究蜕膜和子宫肌层中不同的趋化因子表达如何局部调节树突状细胞的运输(目标4)。了解树突状细胞在母胎界面的行为是如何专门化的，不仅有助于解释胎儿如何在怀孕期间逃避排斥反应，这是当代免疫学中一个尚未解决的主要问题，而且可能有助于阐明树突状细胞在身体其他部位周围组织中的局部调控。

DESCRIPTION (provided by applicant): How the fetus and placenta escape rejection during pregnancy likely involves local immune regulation within the maternal decidua, the specialized stromal tissue that surrounds the implanted embryo. Surprisingly, virtually nothing is known about dendritic cells at the maternal/fetal interface, despite the critical importance of this cell type in monitoring peripheral tissue for foreign antigens and controlling subsequent immune responses. Here, we use TCR-transgenic T cell adoptive transfers and a model antigen transgenic system to test whether an antigen expressed exclusively by the fetus and placenta is indeed presented by dendritic cells within the draining lymph nodes of the uterus, and whether the T cell response is tolerogenic or immunogenic (Aim 1). We will then directly characterize the phenotype of decidual dendritic cells and ask whether these cells appropriately mature and emigrate from the uterus under inflammatory and homeostatic conditions (Aim 2). Third, we will characterize the differential recruitment of dendritic cells to the decidua versus the overlying myometrium, and determine the fate of newly recruited progenitor cells (Aim 3). Lastly, we will study how differential chemokine expression in the decidua and myometrium might locally regulate dendritic cell trafficking (Aim 4). An understanding of how dendritic cell behavior is specialized at the maternal/fetal interface might not only help explain how the fetus escapes rejection during pregnancy, a major unsolved question in contemporary immunology, but will likely shed light onto the local regulation of dendritic cell function in peripheral tissues elsewhere in the body.