Tyrosine Kinases in Autoimmunity

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DESCRIPTION (provided by applicant): Immunological diseases where the immune system responds inappropriately, such as some allergic and autoimmune disorders, display aberrant T cell antigen receptor (TCR/CD3)-induced signaling events. These may include intracellular Ca++ mobilization and the reorganization of the actin cytoskeleton. The protein tyrosine kinase Itk is a critical regulator of these events. Therefore, we believe studies on Itk are important to our understanding of such immunological diseases. We propose the hypothesis that Itk regulates important TCR/CD3-induced signal transduction events including intracellular Ca++ mobilization and reorganization of the actin cytoskeleton. Furthermore, we propose that Itk regulates these events through its various structural domains. In view of this hypothesis the present proposal will address the following three specific aims: 1) Structural requirements of Itk on T cell development and activation. We will reconstitute Itk-deficient mice with selected mutant Itk transgenes that have been shown to display interesting phenotypes. Reconstituted mice will be tested for effects on T cell development, activation, transcriptional activation and cytokine production, TCR-proximal signaling events, and in vivo responses to viral infection. 2) Structural requirements of Itk on the modulation of allergic asthma. For these studies we will utilize the Itk transgenic mice of specific aim 1. Reconstituted mice will be challenged in an experimental model of allergic asthma and the effects of various Itk transgene expression on lung pathology, T cell proliferation, and cytokine production will be determined. 3) Involvement of Itk in TCR/CD3-induced cytoskeletal events. We will assess the involvement of Itk on TCR/CD3-induced actin polymerization, the inducible interaction of Itk with WASP, the interaction of WASP with other actin-polymerization related proteins (e.g. VASP and Arp2/3), and the Ilk structural requirements for these interactions, the role of the Itk-mediated phosphorylation of WASP on actin polymerization, and the involvement of Itk in TCR/CD3-mediated activation of small GTPases and the nucleotide exchange factor Vav.