Dendritic cell behavior at the maternal/fetal interface

描述（由申请人提供）：胎儿和胎盘在怀孕期间如何逃避排斥反应可能涉及母体蜕膜内的局部免疫调节，蜕膜是包围植入胚胎的特殊间质组织。令人惊讶的是，尽管树突状细胞在监测外周组织的外源抗原和控制随后的免疫反应方面具有至关重要的作用，但人们对母体/胎儿界面的树突状细胞几乎一无所知。在这里，我们使用了tcr转基因T细胞过继转移和一个模型抗原转基因系统来测试一种仅由胎儿和胎盘表达的抗原是否确实由子宫引流淋巴结内的树突状细胞呈递，以及T细胞反应是耐受原性的还是免疫原性的（目的1）。然后，我们将直接表征蜕膜树突状细胞的表型，并询问这些细胞是否在炎症和稳态条件下适当地成熟并从子宫迁出（目的2）。第三，我们将描述树突状细胞向蜕膜和上覆肌层募集的差异，并确定新募集的祖细胞的命运（目的3）。最后，我们将研究蜕膜和肌层中趋化因子的差异表达如何局部调节树突状细胞运输（Aim 4）。了解树突状细胞的行为是如何在母体/胎儿界面上特化的，不仅可以帮助解释胎儿在怀孕期间如何逃避排斥反应，这是当代免疫学的一个主要未解决的问题，而且可能会揭示身体其他部位外周组织中树突状细胞功能的局部调节。

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.