B lymphocytes and the antibodies they produce play a critical role in host defense against microbes and in autoimmune diseases. A hallmark of adaptive immunity is heterogeneity of cell fate among antigen-experienced B cells. 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 early B cell-mediated immune response.
The aims will examine whether a deterministic mechanism is used to diversify the initial class switch choices of sibling B cells, and whether asymmetric division i used to meet the opposing demands of terminal differentiation and self-renewal. This project will also examine whether ancestral regulators of cell polarity are responsible for establishing cell biological features necessary for asymmetric 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 and 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)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI076458-06
Application #
8915928
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Lin, Wen-Hsuan W; Adams, William C; Nish, Simone A et al. (2015) Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation. Cell Rep 13:2203-18
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
Paley, Michael A; Kroy, Daniela C; Odorizzi, Pamela M et al. (2012) Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338:1220-5
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
Barnett, Burton E; Ciocca, Maria L; Goenka, Radhika et al. (2012) Asymmetric B cell division in the germinal center reaction. Science 335:342-4
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
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

Showing the most recent 10 out of 11 publications