T lymphocytes play a critical role in host defense against microbes and cancer. A remarkable feature of the signals that trigger T cell participation in the immune response is that every cell appears to have a mandate that assures its daughters will not uniformly adopt the same fate. This proposal develops novel methodologies to image the characteristics of dividing T cells during the course of an infectious disease.
The aims of the project are to test the importance of unequal cellular inheritance in the earliest stages of the immune response, where an abundance of cell fate decisions are being made (Aim 1), in the re-challenge response wherein memory T cells may be mimicking the regenerative behavior of adult stem cells (Aim 2), and in chronic infection because this scenario may tax the regenerative limits of normal memory T cells (Aim 3). The studies proposed herein should offer novel approaches for maintaining lifelong immunity against chronic infections and for eliminating many life-threatening infectious diseases.

Public Health Relevance

T lymphocytes are specialized white blood cells that protect us against infection. These cells need to be able to perform an assortment of functions and to replenish themselves for us to survive in a germ-filled world. This project will provide important information about how these cells can fight off different kinds of germs over the course of our lifetime.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI113365-02
Application #
8852076
Study Section
Immunity and Host Defense (IHD)
Program Officer
Kelly, Halonna R
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
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
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Mittal, Payal; Abblett, Rebecca; Ryan, Joseph M et al. (2018) An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells. J Immunol 200:1513-1526
Kratchmarov, Radomir; Viragova, Sara; Kim, Min Jung et al. (2018) Metabolic control of cell fate bifurcations in a hematopoietic progenitor population. Immunol Cell Biol 96:863-871
Kratchmarov, Radomir; Magun, Arthur M; Reiner, Steven L (2018) TCF1 expression marks self-renewing human CD8+ T cells. Blood Adv 2:1685-1690
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Chen, Yen-Hua; Kratchmarov, Radomir; Lin, Wen-Hsuan W et al. (2018) Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway. Cell Rep 22:860-868
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
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
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
Collins, Amélie; Rothman, Nyanza; Liu, Kang et al. (2017) Eomesodermin and T-bet mark developmentally distinct human natural killer cells. JCI Insight 2:e90063

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