The long-term goal of this project is to elucidate the mechanism(s) by which the invariant natural T (iNKT) cells function in health and disease. iNKT cells are important immunoregulatory innate lymphocytes. They mediate the adjuvant function of a-galactosylceramide (otGalCer), a CDId-restricted glycolipid antigen with potent in vivo immunomodulatory activities against metastatic tumours, certain infections and several autoimmune diseases. The rapid and robust cytokine response of in vivo activated iNKT cells mediates their immunoregulatory function. Instructional processes during ontogeny determine the effector properties of lymphocytes. Our approach to understanding iNKT cell biology has been to elucidate the intercellular and intracellular ontogenetic signals that lead to the development and differentiation of functional iNKT cells. We and others have recently discovered that classical nuclear factor KB (NF-kB) signalling is essential for the maturation and function of iNKT cells but not for conventional T cell ontogeny. This function of NF-kB is largely dependent on NFkB1 (cell autonomous), to a lesser extent on NFkB2, and RelB (cell extrinsic) activities. Therefore, a thorough characterisation of signals that activate NF-kB and its consequences during iNKT cell development and differentiation are essential to our understanding of iNKT cell biology. Here, we will test the central hypothesis that NF-KB is a lineage-specific regulator, which processes and integrates diverse extracellular signals that precisely regulate the development and differentiation of functional iNKT cells. To test this central hypothesis, we will pursue the following three integrated yet independent specific aims: (a) define the mechanism(s) that couples TCR signals to NF-kB activation during iNKT cell ontogeny; (6) define the signals that induce apoptosis in iNKT cells during development;and (c) define the mechanism(s) by which NF-kB regulates functional differentiation of iNKT cells. Upon completion of this project, our expectationis to define the molecular mechanism(s) by which NF-kB regulates the ontogeny and differentiation of functional iNKT cells. These findings will significantly enhance our fundamental understanding of iNKT cell biology and will lead to deeper insights into the molecular mechanisms underlying cell fate specification as well as molecular and functional differentiation within the immune system. Additionally, this knowledge can lead to the development of therapeutics that either enhance (adjuvant effect, downregulate autoimmunity) or suppress (cerebral malaria, airway hypersensitivity) iNKT cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061721-05
Application #
7727376
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Miller, Lara R
Project Start
2005-12-15
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$361,887
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Gilchuk, Pavlo; Hill, Timothy M; Guy, Clifford et al. (2016) A Distinct Lung-Interstitium-Resident Memory CD8(+) T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection. Cell Rep 16:1800-9
Gilchuk, Pavlo; Hill, Timothy M; Wilson, John T et al. (2015) Discovering protective CD8 T cell epitopes--no single immunologic property predicts it! Curr Opin Immunol 34:43-51
Stengel, Kristy R; Zhao, Yue; Klus, Nicholas J et al. (2015) Histone Deacetylase 3 Is Required for Efficient T Cell Development. Mol Cell Biol 35:3854-65
Joyce, Sebastian; Girardi, Enrico; Zajonc, Dirk M (2011) NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. J Immunol 187:1081-9
Gordy, Laura E; Bezbradica, Jelena S; Flyak, Andrew I et al. (2011) IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol 187:6335-45
Boelte, Kimberly C; Gordy, Laura E; Joyce, Sebastian et al. (2011) Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS One 6:e18534
Joyce, Sebastian; Gordy, Laura E (2010) Natural killer T cell-a cat o' nine lives! EMBO J 29:1475-6
Hoek, Kristen L; Gordy, Laura E; Collins, Patrick L et al. (2010) Follicular B cell trafficking within the spleen actively restricts humoral immune responses. Immunity 33:254-65
Florence, William C; Xia, Chengfeng; Gordy, Laura E et al. (2009) Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands. EMBO J 28:3579-90

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