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.
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.
|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|
|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|
|Nish, Simone A; Zens, Kyra D; Kratchmarov, Radomir et al. (2016) CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions. J Exp Med :|
|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|
|Wang, Nathaniel S; McHeyzer-Williams, Louise J; Okitsu, Shinji L et al. (2012) Divergent transcriptional programming of class-specific B cell memory by T-bet and RORÃ½Ã½. Nat Immunol 13:604-11|
|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|
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