The CD8+ T cell response to intracellular pathogens such as bacteria, viruses and protozoan parasites is an essential component of host resistance. This proposal utilizes experimental infectious disease models of bacteria, Listeria monocytongenes, and Vaccinia virus to address questions about the host CD8+ T cell immune response against potential microbial agents of bioterrorism. We have discovered that E protein transcription factors and their inhibitor, Id2, regulate the CD8+ T cell response to intracellular pathogens, which is a novel function for these proteins. It is our goal to understand at a molecular level how this family of transcriptional regulators influences the activation, proliferation, differentiation and survival of CD8+ T cells as they transition from naove to effector to memory cells. While the E proteins are known to regulate many key developmental check-points, lineage commitment, proliferation and survival during hematopoiesis and lymphocyte development, the function of these important proteins is unexplored in the mature T cell. We hypothesize that the activation of CD8+ T cells and subsequent generation of memory cells during the immune response involves the regulation of E protein- transcriptional targets. To gain insight into the specific E protein-transcription factors that regulate gene expression, the genes which are regulated by their activity during the CD8+ T cell response and how the inhibition of their activity regulates memory T cell formation, we propose to:
Aim 1 : Determine which E proteins regulate the in vivo CD8+ T cell response. We will examine the immune response by E2A, E2-2 and HEB-deficient T cells and the DNA-binding activity of each of these proteins during infection with Listeria monocytogenes and Vaccinia virus.
Aim 2 : Identify the molecular pathways controlled by E protein-transcription factors during the in vivo CD8+ T cell immune response to infection.
Aim 3 : Create an Id2-reporter mouse line to define the Id2 expression pattern during the immune response and determine if Id2 expressing effector T cells are the precursors to memory T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072117-04
Application #
7999273
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Ferguson, Stacy E
Project Start
2007-12-15
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$424,974
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Phan, Anthony T; Doedens, Andrew L; Palazon, Asis et al. (2016) Constitutive Glycolytic Metabolism Supports CD8(+) T Cell Effector Memory Differentiation during Viral Infection. Immunity 45:1024-1037
Phan, Anthony T; Goldrath, Ananda W (2015) Hypoxia-inducible factors regulate T cell metabolism and function. Mol Immunol 68:527-35
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Omilusik, Kyla D; Shaw, Laura A; Goldrath, Ananda W (2013) Remembering one's ID/E-ntity: E/ID protein regulation of T cell memory. Curr Opin Immunol 25:660-6
Doedens, Andrew L; Phan, Anthony T; Stradner, Martin H et al. (2013) Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14:1173-82
Cowburn, Andrew S; Takeda, Norihiko; Boutin, Adam T et al. (2013) HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A 110:17570-5
Hess Michelini, Rodrigo; Doedens, Andrew L; Goldrath, Ananda W et al. (2013) Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med 210:1189-200
Best, J Adam; Blair, David A; Knell, Jamie et al. (2013) Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat Immunol 14:404-12

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