Cell Surface Receptors on T Cells and Macrophages

描述（由申请人提供）：信号淋巴细胞活化分子（SLAM或CD 150）是T细胞和专职抗原呈递细胞（APC）之间界面的自身配体受体。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。--针对SLAM的单克隆抗体作为T细胞受体驱动的DNA合成和细胞因子基因活化的共刺激物以CD 28非依赖性方式起作用。SLAM的胞质尾区结合T细胞中的SAP（SH 2D 1A）和APC中的EAT-2。这些单一的游离SH 2结构域蛋白可以作为天然抑制剂或适配器。当SAP基因被改变或缺失时，会发生原发性免疫缺陷，即X-连锁恶性增殖性（XLP）疾病。SLAM是麻疹病毒的主要受体，麻疹病毒引起严重的免疫抑制。本申请中提出的实验旨在了解SLAM对T辅助细胞和APC功能的贡献。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. 少校此外，SLAM在特异性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。具体的目的是：目的#1测试假设，巨噬细胞和T辅助细胞的功能在SLAM缺陷小鼠受损。 目的#2检验SLAM信号转导调节T细胞中的IL-4和IFN γ基因以及巨噬细胞中的IL-12和TNF α基因的假设。 目的#3确定T细胞和巨噬细胞中SLAM相关信号转导蛋白集合体的功能。

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.