The long-term goal of this project is to understand how CD1d controls the immune regulatory function of Va14Ja18 NKT cells. In this application we propose to test the central hypothesis that the natural Va14Ja18 NKT cell antigen is a glycosphingolipid whose assembly with CD1d in MHC class II-enriched vesicles (CIIV/MIIC) requires lipid and protein chaperones. The rationale for this hypothesis is that CD1d controls the immune functions of NKT cells by presenting a putative self lipid antigen(s) whose chemical structure remains unknown. Currently, of all the lipid antigens known, only the synthetic anti-tumor agent alpha-galactosylceramide (alphaGalCer) activates almost all Va14Ja18 NKT cells. Current data suggest that CD1d assembles with invariant chain and/or phospholipids in the ER and exchanges these ligands for another cellular lipid in the CIIV/MIIC. Thence the antigen-loaded CD1d is presented to NKT cells. The chemical nature of the self lipid antigen(s) presented by CD1d to Va14Ja18 NKT cells and the mechanism(s) for biosynthetic assembly of CD1d1 as well as antigen loading in the CIIV/MIIC currently remain outstanding, unanswered questions of major immunological import. Our strategy to test the central hypothesis of this project will be to: a) Define the chemical structure of a natural Va14Ja18 NKT cell antigen to test the hypothesis that a natural antigen is a glycosphingolipid, b) Define the immune functions of a putative Va14Ja18 T cell ligand, thereby test the hypothesis that alpha-glucosylceramide is a natural antigen, c) Determine the mechanism(s) underlying the biosynthetic assembly of CD1 and the assembly of CD1d with antigen to test the hypothesis that this assembly requires lipid and protein chaperone(s), d) Define the molecular/structural features of the Va14Ja18 NKT cell receptor-antigen interface to test the hypothesis that co-operative antigen-TcR interaction, which permits sensitive antigen recognition, involves allosteric change at the ligand-receptor interface. Thus the goals of this proposal have the potential of providing fundamental new insights into our understanding of immune recognition, response and regulation. In keeping with our long-term goal, upon completion of this project we expect to elucidate the mechanism by which CD1d1 assembles in vivo and controls Va14Ja18 NKT cell function. Additionally, the identification of a natural antigen could lead to the development of natural therapeutics replacing alphaGalCer, which has been demonstrated to prevent the onset of several autoimmune diseases including type I diabetes and experimental autoimmune encephalomyelitis. Together, they will significantly advance our understanding of the physiological role of the CD1 antigen presentation system and NKT cells within the context of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042284-06A1
Application #
6631032
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Winter, David B
Project Start
1998-08-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
6
Fiscal Year
2003
Total Cost
$151,000
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
Gilchuk, Pavlo; Knight, Frances C; Wilson, John T et al. (2017) Eliciting Epitope-Specific CD8+ T Cell Response by Immunization with Microbial Protein Antigens Formulated with ?-Galactosylceramide: Theory, Practice, and Protocols. Methods Mol Biol 1494:321-352
Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M et al. (2017) Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective. Front Immunol 8:1858
Li, Bo; Siuta, Michael; Bright, Vanessa et al. (2016) Improved proliferation of antigen-specific cytolytic T lymphocytes using a multimodal nanovaccine. Int J Nanomedicine 11:6103-6121
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
Hastings, Andrew K; Gilchuk, Pavlo; Joyce, Sebastian et al. (2016) Novel HLA-A2-restricted human metapneumovirus epitopes reduce viral titers in mice and are recognized by human T cells. Vaccine 34:2663-70
Joyce, Sebastian (2015) Immunoproteasomes edit tumors, which then escapes immune recognition. Eur J Immunol 45:3241-5
Erickson, John J; Lu, Pengcheng; Wen, Sherry et al. (2015) Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype. J Immunol 195:4319-30
Wen, Sherry C; Schuster, Jennifer E; Gilchuk, Pavlo et al. (2015) Lung CD8+ T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8+ T Cells. J Virol 89:8713-26
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
Hill, Timothy M; Gilchuk, Pavlo; Cicek, Basak B et al. (2015) Border Patrol Gone Awry: Lung NKT Cell Activation by Francisella tularensis Exacerbates Tularemia-Like Disease. PLoS Pathog 11:e1004975

Showing the most recent 10 out of 23 publications