The ultimate outcome of T cell receptor engagement (TCR) is dictated not by the antigen but rather by the context in which the antigen is encountered. T cells that recognize antigen presented by activated APCs in the context of costimulation are activated, while T cells that recognize antigen presented by resting APCs are rendered tolerant. Our lab is interested in dissecting the pathways involved in TCR-induced tolerance vs activation. This proposal will focus on the role of the transcription factors Egr-2 and Egr-3 in inducing T cell anergy as well as the co-repressor/coactivator molecule NAB2 in facilitating TCR induced activation. Using T cell clones we will examine the regulation of Egr-2 and Egr-3 in anergic and non-anergic cells. We will inducibly overexpress Egr-2 and Egr-3 in order to demonstrate that these factors are the cyclosporin sensitive component of T cell anergy. In addition, we will utilize T cells from Egr-2 and Egr-3 knockout mice in order to determine the affect of these factors on T cell activation and tolerance induction. In order to determine the effect of these factors in vivo we will adoptively transfer TCR transgenic T cells from Egr- knockout mice into animals which have a tumor expressing cognate antigen. Using this system we will assess the abilities of such cells to eradicate tumor as well as their susceptibility to tumor induced tolerance. NAB2, was originally discovered as a protein which binds to and can either co-repress or co-activate Egr mediated transcription. Indeed, we have generated preliminary data that NAB2 is upregulated by TCR engagement and that the overexpression of NAB2 leads to an increase in IL-2 promoter mediated transcription. In this proposal we will characterize the regulation of NAB2 in T cells as well as its effects on T cell activation and the induction of tolerance. Furthermore, we will assess the ability of T cells which overexpress NAB2 to eradicate tumor in vivo. Understanding the discreet pathways that lead to activation and tolerance should provide insight into devising specific clinical interventions. In the case of cancer immunotherapy, the goal is to inhibit tumor induced tolerance while at the same time enhance tumor specific T cell activation. On the other hand, in transplantation and autoimmunity, the objective is to inhibit T cell activation while at the same time promote TCR induced tolerance.
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