Our laboratory has been interested in the TCR-induced signaling pathways that lead to an immune response versus tolerance. During the course of our studies we have identified the transcription factors Early Growth Response 2 and 3 (Egr-2 and Egr-3) as TCR-induced inhibitors of T cell activation. Furthermore, we have identified NAB2, a coactivator of Egr-1 mediated transcription, as a novel activator of T cell function. We propose that these factors play a critical role in determining the outcome of antigen recognition. Specifically we hypothesize that TCR-induced Egr-1 and NAB2 promote an activating genetic program by inducing genes that enhance T cell function and repressing genes that inhibit activation. Likewise, we propose that Egr-2 and Egr-3 promote a negative regulatory program by inducing genes that inhibit T cell function and repressing genes that promote activation.
In Aim I we will test the hypothesis that mechanistically, Egr-2 and Egr-3 inhibit T cell function and promote anergy in Th1 cells by repressing IL-2 transcription and inducing the upregulation of the E3 ligases. While we have established a role for Egr-2 and Egr-3 in determining the anergic fate of Th1 cells stimulated with Signal 1 alone, new preliminary data indicate a role for Egr-3 in promoting Th17 induction in naive T cells. Thus, we will also define the mechanism by which Egr-3 (and potentially Egr-2) regulates Th17 development.
In Aim II, we will test the hypothesis that mechanistically NAB2 promotes T cell function by simultaneously up regulating activating genes and repressing inhibitors of T cell activation. In addition we will test the hypothesis that NAB2 can inhibit T cell tolerance in vivo.
In Aim III, we will test the hypothesis that tumor-induced tolerance is mediated by Egr-2 and Egr-3 and that the NAB2 can enhance tumor immunity. In addition, by generating an Egr-2-eGFP expressing mouse, we will be able to track and functionally and biochemically interrogate anergic and activated tumor antigen specific T cells in vivo. Overall the understanding of these pathways will potentially help to identify targets for novel immunoregulatory drugs. In the case of autoimmunity, the design of pharmacologic inhibitors that block T cell activation and promote T cell tolerance while in the case of tumor-immunity the identification of pharmacologic inhibitors that block tumor induced tolerance and thereby enhance immunotherapy.
We have identified Egr-2 and Egr-3 and NAB2 as novel regulators of T cell activation and tolerance. In this proposal we will determine the mechanism by which they mediate their effects both in vitro and in vivo. Overall the understanding of these pathways will potentially help to identify targets for novel immunoregulatory agents in order to treat autoimmunity and prevent transplantation rejection as well as enhance anti-tumor immunotherapy.
|Leone, Robert D; Lo, Ying-Chun; Powell, Jonathan D (2015) A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J 13:265-72|
|Parkinson, Rose M; Collins, Samuel L; Horton, Maureen R et al. (2014) Egr3 induces a Th17 response by promoting the development of Î³Î´ T cells. PLoS One 9:e87265|
|Ananieva, Elitsa A; Patel, Chirag H; Drake, Charles H et al. (2014) Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J Biol Chem 289:18793-804|
|Delgoffe, Greg M; Kole, Thomas P; Zheng, Yan et al. (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832-44|
|Zheng, Yan; Delgoffe, Greg M; Meyer, Christian F et al. (2009) Anergic T cells are metabolically anergic. J Immunol 183:6095-101|
|Delgoffe, Greg M; Kole, Thomas P; Cotter, Robert J et al. (2009) Enhanced interaction between Hsp90 and raptor regulates mTOR signaling upon T cell activation. Mol Immunol 46:2694-8|
|Zarek, Paul E; Huang, Ching-Tai; Lutz, Eric R et al. (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111:251-9|
|Collins, Sam; Lutz, Michael A; Zarek, Paul E et al. (2008) Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol 38:528-36|
|Zheng, Yan; Collins, Samuel L; Lutz, Michael A et al. (2007) A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 178:2163-70|
|Collins, Samuel; Wolfraim, Lawrence A; Drake, Charles G et al. (2006) Cutting Edge: TCR-induced NAB2 enhances T cell function by coactivating IL-2 transcription. J Immunol 177:8301-5|
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