B lymphocytes and the antibodies they produce play a critical role in host defense. Cell fate diversification of activated lymphocytes is essential to achieve the regenerative state required for long-lived immunity. The mechanisms responsible for generating B cell fate diversity, however, are poorly understood. Substantial preliminary data suggest B cells can diversify the fates and functions of their daughter cells using an evolutionarily conserved strategy to allocate unequal amounts of key components. This project will test whether asymmetric cell division is a cardinal feature of the B cell- mediated immune response. The proposal develops novel methodologies to image the characteristics of dividing B cells during the course of an immune response.
The aims of the project are to test the importance of unequal cellular inheritance of three different transcriptional regulators of B cells Bcl-6, Pax5, and T-bet, each of which is known to regulate critical cell fate decisions. The experiments will test the hypotheses that asymmetric division is iteratively used to meet the opposing demands of terminal differentiation and self-renewal, as well to refine and diversify the functional properties of antibodies by regulating germinal center entry and class switch choice. This project will also examine whether ancestral regulators of cell polarity are responsible for establishing asymmetric B cell division, and how asymmetrically inherited proteins could mediate fate disparity in daughter B cells. These studies should provide a framework for rational engineering of immune responses and vaccines against microbial agents. This project should also address fundamental uncertainties regarding the principle of clonal selection of lymphocytes in response to infectious diseases or during situations when our immune cells attack our own selves.

Public Health Relevance

B lymphocytes are specialized white blood cells that protect us against infection. These cells need to be able to replenish themselves for vaccines to work properly. This project will provide important information about how these cells provide long-term immunity after we are vaccinated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076458-10
Application #
9636419
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2007-12-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
10
Fiscal Year
2019
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
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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