A hallmark of adaptive immunity is heterogeneity of T cell fates in response to microbial pathogens. This goal of this project is to understand the molecular basis by which these cell fate decisions are made. Preliminary data has suggested that asymmetric cell division might be a mechanism utilized by T cells to generate cell fate heterogeneity during immune responses to microbial pathogens. Asymmetric cell division is an evolutionary conserved mechanism used to confer disparate fates among daughter cells. This mechanism involves the polarized alignment of determinants of cell fate perpendicular to the mitotic spindle, thus ensuring the unequal inheritance of critical molecules and divergence of daughter cell fate. Activation of a naive T cell by its antigen-presenting cell (ARC)during an immune response is characterized by polarization of immune receptors and signaling molecules to the site of contact. Recent in vivo imaging studies suggest that an activated T cell engages in sustained contact with ARC until its first cellular division. This proposal tests the hypothesis that this prolonged contact of the T cell with ARC coordinates the asymmetric partitioning of proteins that mediate signaling, cell fate specification, and asymmetric cell division. In this way, asymmetric T cell division during an immune response could give rise to daughter cells with distinct fates and ensure that appropriate diversity of cell fate arises from the descendants of a single lymphocyte. This proposal aims to answerthree questions. First, is asymmetric cell division a universal feature of the initial divisions of the CD4+ T cell response to microbial pathogens? This will be addressed by using immunofluorescence microscopy to determine whether asymmetric cell division is evident in CD4+ T cells responding to various microbial pathogens in vivo. Second,what are the fates of the initial daughter and granddaughter CD4+ T cells? This will be addressed by characterizing daughter cells, sorted by flow cytometry, arising from initial asymmetric T cell divisions of the immune response. Third, is there a role for asymmetric cell division in the differentiation of colitogenic CD4+ T cells? This will be addressed by characterizing the morphology and fates of activated CD4+T cells in an animal model of colitis. Intestinal microbes trigger an aberrant CD4+ T cell immune response that ultimately leads to inflammatory bowel disease (IBD). The goal of this proposal is to understand how cell fate decisions are made during an immune response and how distinct T cell subsets that cause or prevent IBD are generated. Understanding the mechanism bywhich this occurs is likely to provide important insights into the pathogenesis of IBD and may identify new targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK080949-06
Application #
8309393
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$110,916
Indirect Cost
$8,216
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Arsenio, Janilyn; Kakaradov, Boyko; Metz, Patrick J et al. (2014) Early specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single-cell gene-expression analyses. Nat Immunol 15:365-72
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
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
Cantor, Joseph; Slepak, Marina; Ege, Nil et al. (2011) Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. J Immunol 187:851-60