Receptors Of Plasmacytoid Dendritic Cells And Their Ligands

描述(申请人提供)：浆细胞样树突状细胞(PDCs)代表一种特殊的免疫细胞群，能产生大量的I型干扰素(干扰素)来应对病毒，并作为天然免疫和获得性免疫之间的关键联系。我们的长期目标是研究pDC在特定生理环境或条件下的功能。核心假设是，独特的PDC受体通过与其配体相互作用并激活特定的细胞内途径，在PDCs的生物学功能中发挥关键作用。我们的假设基于这样的观察：1)人PDC受体ILT7激活ITAM介导的信号通路以抑制pDC的干扰素反应；2)ILT7的潜在配体在一组人乳腺癌细胞系中表达；3)人PDC受体BDCA2是一种未知配体的C型凝集素，可能利用ITAM介导的机制调节pDC的干扰素反应。其具体目的是：1)确定ILT7在人pDC中的详细信号机制，并研究ITAM介导的途径与Toll样受体(TLR)介导的天然免疫反应的基本机制。2)鉴定人乳腺癌细胞表达ILT7的天然配体，并研究其组织表达与PDC侵袭的关系。通过与ILT7的相互作用，该配体在pDC上的作用将被彻底阐明。3)确定BDCA2使用的详细信令机制。BDCA2的天然配体将使用能够检测表面BDCA2结合的报告细胞系统进行筛选。在这一目标中，将测试广泛的碳水化合物结构、微生物制剂和细胞相关因子。PDC的存在和功能改变与自身免疫性疾病、传染病和癌症等人类疾病有关。通过寻找其配体和共同的细胞内信号转导机制，聚焦于人PDCs独特表达的两种表面受体，将极大地促进PDCs生理功能的研究，并可能产生具有治疗潜力的直接分子靶点。

DESCRIPTION (provided by applicant): Plasmacytoid dendritic cells (pDCs) represent a specialized immune cell population that produces large amounts of type I interferons (IFN) in response to viruses and function as a critical linkage between innate and adaptive immunity. Our long-term goal is to study the functions of pDCs pertaining to specific physiological environments or conditions. The central hypothesis is that unique pDC receptors play key roles in the biological functions of pDCs through interactions with their ligands and activating specific intracellular pathways. We based that hypothesis on the observation that 1) human pDC receptor ILT7 activates an ITAM-mediated signaling pathway to inhibit IFN responses by pDCs, 2) the potential ligand of ILT7 is expressed by a group of human breast cancer cell lines, and 3) human pDC receptor BDCA2, a C-type lectin with unknown ligand, potentially utilizes the ITAM-mediated mechanism to regulate pDCs' IFN responses. The specific aims are to: 1) Determine the detailed signaling mechanism of ILT7 in human pDCs and study the underlining mechanism how ITAM-mediated pathway intersects with the Toll-like receptor (TLR)-mediated innate immune responses. 2) Identify the natural ligand of ILT7, which is expressed by human breast cancer cell lines, and study its tissue expression in relation with pDC infiltration. The function of the ligand on pDCs through interaction with ILT7 will be thoroughly elucidated. 3) Determine the detailed signaling mechanism used by BDCA2. The natural ligand for BDCA2 is to be screened using a reporter cell system capable of sensing surface BDCA2 engagement. A wide range of carbohydrate structures, microbial agents and cell-associated factors will be tested in this aim. The altered presence and functions of pDCs have been implicated in human ailments such as autoimmune diseases, infectious diseases and cancer. By focusing on the two surface receptors uniquely expressed by human pDCs through pursuing their ligands and shared intracellular signaling mechanism, the proposed studies will greatly advance research on the physiological functions of pDCs and may generate direct molecular targets with therapeutic potential.