THRESHOLD CONTROL FOR T CELL ANTIGEN RECEPTOR

Medical College Of Georgia (Mcg), Augusta GA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Investigator's abstract): The long-term goal is to identify the mechanism that defines the difference of cellular responses induced by stimulation of T-cell antigen receptor (TCR). Engagement of TCR initiates at least two different types of responses. Antigenic peptides (agonist)/MHC complexes induce mature T-cells to produce IL-2, to express surface proteins such as CD25 (IL-2 receptor a chain) and CD69, and to proliferate. In contrast, partial agonist or antagonist induces expression of these surface antigens but not other responses. In some case, partial agonists transform T-cells functionally so that they do not respond to agonist (a.k.a. anergic state). The investigator will take the approach of analyzing the signaling process through the TCR to determine the signals only involved in the full activation of T-cells. ZAP-70, a cytoplasmic protein tyrosine kinase (PTK), is an essential molecule for TCR signal transduction. While characterizing the function of this PTK, the investigator found that Shc, an adaptor molecule, is a substrate for ZAP-70 and established a mutant T-cell line lacking expression of Shc protein. Study 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. The phenotype of this mutant cell line is indistinguishable from that which has been described as the partial activation of peripheral T-cells. Based on preliminary results, the investigator hypothesizes that the involvement of the Shc signaling pathway is a determining factor to provoke full activation of T-cells and that it is the absence of the Shc signaling pathway that differentiates the full T-cell response from that of partial agonist stimulation. To test this hypothesis, the investigator will determine the mechanism of how Shc functions to induce the IL-2 gene and measure the influence of Shc pathway activation on partial agonist stimulation. Completion of this study will contribute to the understanding of mechanisms that establish immunological self-tolerance and elicit an immune response. This will provide key information to understand the etiology of autoimmune diseases and its prevention and treatment and will contribute to establish the procedure to provoke anti-cancer immune responses.