Mechanisms of Integrin-Mediated Costimulation in T Cells

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DESCRIPTION (provided by applicant): The integrin 1421 (VLA-4) contributes to the etiology of common autoimmune disorders, including multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. Although VLA-4 is widely viewed as contributing to T cell function by directing cell trafficking and by enhancing cell adhesion, VLA-4 potently costimulates T cell activation. The mechanisms underlying this costimulation are not well understood and may play a significant role in the etiology of human immune disorders. Our long-range goal is to understand how to manipulate the costimulatory functions of VLA-4 in order to regulate T cell activation in vivo. Our immediate objective is to determine how VLA-4 modulates T cell responses to antigen. Here, we present preliminary data characterizing a previously unknown effect of VLA-4 ligation on the movement of signaling complexes induced by the TCR. Our specific hypothesis is that structures containing SLP-76 and ADAP are required for the transmission of tension-dependent costimulatory signals initiated upon VLA-4 ligation. The rationale for the proposed work is that it will provide an enhanced understanding of the fundamental mechanisms that enable the integration of the signaling pathways downstream of the TCR and VLA-4. Three aims will examine how ADAP contributes to T cell costimulation and how cytoskeletal tension contributes to VLA-4 dependent costimulatory signals: 1) How does ADAP contribute to the assembly and translocation of SLP-76 microclusters? 2) How does costimulation depend on the VLA-4-dependent immobilization of microclusters? 3) How does cytoskeletal tension contribute to T cell costimulation by VLA-4? These studies explore a novel effect of VLA-4 ligation, the lateral immobilization of TCR-induced complexes, and use it as a tool to dissect the pathways involved in costimulation by VLA-4. We expect these studies to define the mechanisms by which VLA-4 ligation costimulates T cell activation. This will have a positive impact on our understanding of autoimmune disease, and will assist in the identification of unique intracellular targets for drug development. This work will also generate insights into the systems linking cell shape to cell growth and proliferation, providing useful insights into cancer. PUBLIC HEALTH RELEVANCE: Immune responses normally protect against pathogens and tumors, but can be activated inappropriately, resulting is inflammatory disorders and autoimmune diseases. Integrins are proteins that help activate T cells, which play a crucial role in the regulation these immune responses. This study will clarify how integrins enhance T cell responses that can contribute to either health or disease. In this manner, we expect to gain useful insights into the underlying causes of common medical conditions, including asthma, multiple sclerosis, diabetes, inflammatory bowel disease, and atherosclerosis.