Cell Surface Receptors on T Cells and Macrophages

描述（由申请人提供）：信号淋巴细胞激活分子（SLAM或cd150）是T细胞和专业抗原呈递细胞（apc）之间界面的自配体受体。SLAM在T细胞和apc中起作用的观点得到以下观察结果的支持：-SLAM缺陷小鼠对利什曼原虫和气道高反应性有异常反应。SLAM抗体阻断小鼠实验性结肠炎的发展。靶向SLAM的单克隆抗体以cd28不依赖的方式作为T细胞受体驱动的DNA合成和细胞因子基因激活的共刺激物。SLAM的细胞质尾部结合T细胞中的SAP （SH2D1A）和apc中的EAT-2。这些单游离sh2结构域蛋白可以作为天然抑制剂或适配器。当SAP基因被改变或删除，原发性免疫缺陷，x连锁淋巴细胞增生性（XLP）疾病，发展。-SLAM是麻疹病毒的主要受体，导致严重的免疫抑制。本应用程序中提出的实验旨在了解SLAM对T辅助细胞和apc功能的贡献。我们的基本策略是研究SLAM对T细胞和巨噬细胞在实验性结肠炎、气道高反应性和L. major感染发病机制中的作用。此外，SLAM在特定细胞因子基因诱导中的作用将在细胞和生化水平上进行剖析。具体目的是：目的1验证巨噬细胞和T辅助细胞功能在slam缺陷小鼠中受损的假设。目的2：验证SLAM信号转导调节T细胞中的IL-4和IFNgamma基因以及巨噬细胞中的IL-12和TNFalpha基因的假设。目的3：确定SLAM相关信号转导蛋白集合在T细胞和巨噬细胞中的功能。

DESCRIPTION (provided by the applicant): Signaling Lymphocyte Activation Molecule (SLAM or CD 150) is a self-ligand receptor at the interface between T cells and professional antigen presenting cells (APCs). The notion that SLAM functions in T cells and APCs is supported by the following observations: --SLAM-deficient mice have abnormal responses to Leishmania major and airway hyper-responsiveness. Antibodies to SLAM block development of experimental colitis in mice. --Monoclonal antibodies directed at SLAM act as co-stimulators of T cell receptor driven DNA synthesis and cytokine gene activation in a CD28-independent manner. --The cytoplasmic tail of SLAM binds SAP (SH2D1A) in T cells and EAT-2 in APCs. These single free SH2-domain proteins can act either as natural inhibitors or as adapters. When the SAP gene is altered or deleted, a primary immunodeficiency, X-linked Lymphoproliferative (XLP) disease, develops. --SLAM is the primary receptor for Measles Virus, which causes a severe immune-suppressionThe experiments proposed in this application are designed to understand the contributions of SLAM to the function of T helper cells and APCs. The fundamental strategy is to examine the in vivo role of SLAM on T cells and macrophages in the pathogenesis of experimental colitis, airway hyper-responsiveness and infections with L. major. Furthermore, the role of SLAM in specific cytokine gene induction will be dissected at the cellular and biochemical level. The specific aims are: Aim# 1 Test the hypothesis that both macrophage and T helper cell functions are impaired in SLAM-deficient mice. Aim#2 Test the hypothesis that SLAM signal transduction regulates the IL-4 and IFNgamma genes in T cells and the IL-12 and TNFalpha genes in macrophages. Aim#3 Determine the function of the SLAM associated signal transduction protein ensemble in T cells and macrophages.