Cell Surface Receptors on T Cells and Macrophages

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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.