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.

National Institute of Health (NIH)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Kelly, Halonna R
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Chaix, Julie; Nish, Simone A; Lin, Wen-Hsuan W et al. (2014) Cutting edge: CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal. J Immunol 193:1013-6
Paley, Michael A; Gordon, Scott M; Bikoff, Elizabeth K et al. (2013) Technical Advance: Fluorescent reporter reveals insights into eomesodermin biology in cytotoxic lymphocytes. J Leukoc Biol 93:307-15
Curran, Michael A; Geiger, Theresa L; Montalvo, Welby et al. (2013) Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J Exp Med 210:743-55
Ciocca, Maria L; Barnett, Burton E; Burkhardt, Janis K et al. (2012) Cutting edge: Asymmetric memory T cell division in response to rechallenge. J Immunol 188:4145-8
Gordon, Scott M; Chaix, Julie; Rupp, Levi J et al. (2012) The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36:55-67
Chang, John T; Ciocca, Maria L; Kinjyo, Ichiko et al. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34:492-504
Kao, Charlly; Oestreich, Kenneth J; Paley, Michael A et al. (2011) Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 12:663-71
Gordon, Scott M; Carty, Shannon A; Kim, Jiyeon S et al. (2011) Requirements for eomesodermin and promyelocytic leukemia zinc finger in the development of innate-like CD8+ T cells. J Immunol 186:4573-8
Banerjee, Arnob; Gordon, Scott M; Intlekofer, Andrew M et al. (2010) Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 185:4988-92
Kinjyo, Ichiko; Gordon, Scott M; Intlekofer, Andrew M et al. (2010) Cutting edge: Lymphoproliferation caused by Fas deficiency is dependent on the transcription factor eomesodermin. J Immunol 185:7151-5

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