Threshold control for T cell antigen receptor

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DESCRIPTION: (Adapted from Applicant's Abstract) My long-term career goal is to elucidate the mechanisms of how the immunological repertoire is formed. The recognition of antigen by T cells plays a critical role to determine the fate of each T cell clone and to ultimately establish the repertoire of the immune system. Thus, I have focused my research on the T cell antigen receptor (TCR)- derived signals that determine T cell fate. The immediate goal is to identify the mechanism that defines the two different types of T cell responses. Antigenic peptides (agonist) induce full activation of mature T cells to produce IL-2, to express surface proteins such as CD25 (IL-2 receptor alpha chain) and CD69, and to proliferate. In contrast, partial agonist peptides induce expression of the surface antigens but not other responses. The research proposed here will determine the signals exclusively involved in the agonistic activation of T cells. ZAP-70, a cytoplasmic protein tyrosine kinase (PTK), is an essential molecule for TCR signal transduction. Preliminary results show that an adapter molecule Shc is a substrate of ZAP-70. My laboratory established a mutant T cell line lacking expression of Shc. Studies of this cell line revealed that Shc is indispensable for IL-2 production by TCR stimulation, but is not required for expression of other genes. I hypothesize that the involvement of the Shc signaling pathway is a determining factor to provoke agonistic activation of T cells and that it is the absence of the Shc signaling pathway that differentiates the full T cell response from the partial response. To test this, I will determine the mechanism whereby Shc functions to induce IL-2 gene expression and identify the biological effect of loss of Shc in mice. Completion of this study will provide information to understand the etiology of autoimmune diseases and immunodeficiencies. The K02 award will help the development of my career in three criteria; (1) Incorporation of rapidly developing genomic/proteomic technology into the analysis of T cell signaling pathway; (2) Extending and developing analytical methods on the signaling events at the single cell level; (3) Determining the significance of TCR signaling events in human immune disorders.