CD8+ T cells play a critical role in host defense against microbes pertinent to biodefense. A hallmark of adaptive immunity against agents such as Listeria monocytogenes, LCMV virus, and Toxoplasma gondii is heterogeneity of cell fate among antigen-experienced CD8+ T cells. Substantial preliminary evidence outlined in this proposal indicates that the first division of a CD8+ T cell responding to a pathogen, in vivo, is characterized by unequal partitioning of proteins with established roles in signaling, cell fate specification, and asymmetric cell division. In addition, the first daughter T cells of the immune response appear to be differentially fated as precursors of the effector and memory lineages. This project will test whether asymmetric cell division is a general feature of the CD8+ T cell response against pathogens, whether ancestral regulators of cell polarity are responsible for establishing cytoskeletal features necessary for asymmetric division, and how asymmetrically inherited signaling proteins could mediate fate disparity in daughter T cells. These studies should provide a framework for rational engineering of immune responses and vaccines against agents of biodefense, and address fundamental uncertainties regarding the principle of clonal selection of lymphocytes in response to infectious diseases.

Public Health Relevance

Specialized white blood cells, called lymphocytes, increase in number to help protect us against infections. This project will provide fundamental insight into how immunity against re-infection is maintained for one's entire life. This proposal is a response to a continuing initiative in Biodefense research sponsored by the NIAID.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Yen, Bonnie; Fortson, Katherine T; Rothman, Nyanza J et al. (2018) Clonal Bifurcation of Foxp3 Expression Visualized in Thymocytes and T Cells. Immunohorizons 2:119-128
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
Kumar, Brahma V; Kratchmarov, Radomir; Miron, Michelle et al. (2018) Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities. JCI Insight 3:
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
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

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