Cell-mediated immunity is critical for host defense against all classes of pathogens and cells that have undergone cancerous transformation. Strategies to vaccinate or potentiate T lymphocyte-mediated cellular immunity have been remarkably ineffective, probably owing to our limited understanding of the mechanisms for establishing and maintaining T cell effector function and memory. This proposal investigates how two T- box family transcription factors contribute to the formation of cellular immunity. Eomesodermin and T-bet redundantly ensure CD8+ T cells become cytotoxic effector cells but they also seem to oppose each other's functions in normal and abnormal CD8+ T cell differentiation. This allows the two transcription factors to form an adjustable balance between the opposing demands of terminal differentiation and self-renewal.
The specific aims of this project will address how and when Eomes functions in memory T cell programming.
The aims will also resolve whether the predominant actions of Eomes in memory cells are on a unique set of genes or whether Eomes is controlling CD8+ T cell memory through interplay with T-bet at loci they regulate in common. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in the immune response. It is also anticipated that these studies will yield new strategies for defending us against a variety of infectious diseases that are the focus of our CD8+ T cell responses.

Public Health Relevance

Specialized white blood cells, called lymphocytes, increase in number to help protect us against infections. This project will provide important information about how these cells are programmed for immediate elimination of infections, how they are trained to provide immunity against re-infection for our entire life, and how they can be re-programmed if they become ineffective.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061699-09
Application #
8496667
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Kelly, Halonna R
Project Start
2004-09-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$376,000
Indirect Cost
$141,000
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Nish, Simone A; Lin, Wen-Hsuan W; Reiner, Steven L (2017) Lymphocyte Fate and Metabolism: A Clonal Balancing Act. Trends Cell Biol 27:946-954
Collins, Amélie; Rothman, Nyanza; Liu, Kang et al. (2017) Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI Insight 2:e90063
Nish, Simone A; Zens, Kyra D; Kratchmarov, Radomir et al. (2017) CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J Exp Med 214:39-47
Kratchmarov, Radomir; Nish, Simone A; Lin, Wen-Hsuan W et al. (2017) IRF4 Couples Anabolic Metabolism to Th1 Cell Fate Determination. Immunohorizons 1:156-161
Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M et al. (2016) Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection. J Immunol 197:1017-22
Adams, William C; Chen, Yen-Hua; Kratchmarov, Radomir et al. (2016) Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal. Cell Rep 17:3142-3152
Pikovskaya, Olga; Chaix, Julie; Rothman, Nyanza J et al. (2016) Cutting Edge: Eomesodermin Is Sufficient To Direct Type 1 Innate Lymphocyte Development into the Conventional NK Lineage. J Immunol 196:1449-54
Lau, Colleen M; Nish, Simone A; Yogev, Nir et al. (2016) Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses. J Exp Med 213:415-31
Lin, Wen-Hsuan W; Nish, Simone A; Yen, Bonnie et al. (2016) CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination. Cell Rep 17:1773-1782
Reiner, Steven L (2015) T-bet transcendent: unmasking the faces of multifarious immunity. J Immunol 194:2959-60

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