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细胞和专业抗原提呈细胞(APC)之间的一种自我配基受体。SLAM在T细胞和APC中发挥作用的观点得到了以下观察的支持：--SLAM缺陷的小鼠对主要利什曼原虫和呼吸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的单抗以不依赖于CD28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同刺激物。-SLAM的细胞质尾巴与T细胞中的SAP(SH2D1A)和APC中的EAT-2结合。这些单一的游离SH2结构域蛋白既可以作为天然抑制物，也可以作为接头。当SAP基因改变或缺失时，就会发生一种原发免疫缺陷--X连锁淋巴增生性(XLP)病。--SLAM是麻疹病毒的主要受体，它会导致严重的免疫抑制。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T细胞和巨噬细胞上的SLAM在实验性结肠炎、呼吸道高反应性和主要乳杆菌感染的发病机制中的作用。此外，还将从细胞和生化水平剖析SLAM在特异性细胞因子基因诱导中的作用。具体目标是：目的#1测试SLAM缺陷小鼠的巨噬细胞和T辅助细胞功能受损的假设。目的#2验证SLAM信号转导通路调节T细胞IL-4和IFN-γ基因以及巨噬细胞IL-12和TNFα基因的假说。目的#3确定SLAM相关信号转导蛋白在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.