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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098109-09
Application #
8403648
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2003-04-15
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$257,775
Indirect Cost
$100,595
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Parkinson, Rose M; Collins, Samuel L; Horton, Maureen R et al. (2014) Egr3 induces a Th17 response by promoting the development of ?? T cells. PLoS One 9:e87265
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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
Safford, Meredith; Collins, Samuel; Lutz, Michael A et al. (2005) Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol 6:472-80

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