Novel substrates of the TCR kinase

University Of Pennsylvania, Philadelphia PA

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Abstract

The overall goal of this proposal is to examine various aspects of how the SLP-76 adapter molecule functions during T cell development and in mature T cell function. Prior work from our group identified SLP- 76 as a key molecule necessary for signaling downstream ofthe pre-T cell receptor and T cell receptor. Complete loss of SLP-76 expression due to targeted deletion in a murine model system results in failed thymocyte development early in ontogeny (at the double negative three [DNS] stage). Recent work from our laboratory has resulted in the generation of mice in which the SLP-76 gene was flanked by loxP sites to allow for both lineage specific and temporally controlled deletion ofthe gene. Additionally, in the past three years, we have generated three knock-in mutations of the SLP-76 gene to address the role of this adapter protein in T cell develoment and function. Using these novel genetic tools, three specific aims are proposed. The first aim will be to analyze the impact of specific tyrosine mutations of SLP-76 on CD4+ and CD8+ T cell effector and memory functions. The second aim will probe the mechanisms through which SLP-76 functions by examining the intermolecular interactions mediated by wild type SLP-76 versus the SLP-76 mutant proteins. These studies will provide new insights into how various molecular interactions control the key signaling events that are initiated by T cell receptor engagement and how these signals are translated into effector functions. The third specific aim of this proposal will continue to test the importance of SLP-76 relocalization for immune cell function. For these experiments we will generate additional SLP-76 mutants that alter its location within the cell. Finally, we propose a fourth pilot aim. In these studies we will perform the initial characterization of a previously undescribed cDNA that encodes a molecule with apparent homology to SLP-76.