Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the MHC class l-related protein CD1d. Emerging evidence indicates that iNKT cells play a regulatory role in the immune system. The long-term goal of this proposal is to obtain a better understanding of the in vivo immune response of mice to various stimulators of iNKT cells and to utilize this information for the development of better prophylactic and therapeutic approaches of human disease. Studies from our laboratory have demonstrated that the prototypical iNKT cell antigen, alpha-galactosylceramide (GalCer) can prevent disease in experimental models of type 1 diabetes, multiple sclerosis and lupus. Despite the impact of GalCer treatment on a variety of disease processes, our understanding of the response of iNKT cells themselves to glycolipid antigens is limited. Recent studies from our laboratory have demonstrated that the response of iNKT cells to GalCer activation is characterized by surface receptor down-modulation, expansion, cytokine production, cross-talk with other cells, homeostatic contraction, and acquisition of an anergic phenotype. Guided by these preliminary findings, our proposed studies will test the overall hypothesis that glycolipid activation of iNKT cells initiates a program of anergy induction with long-term effects on subsequent iNKT cell-controlled immune responses. We will test this hypothesis in three integrated Specific Aims:
Aim 1 will determine the cellular interactions that are critical for the induction and maintenance of long-term iNKT cell anergy, Aim 2 will investigate the biochemical mechanisms involved in the induction and maintenance of iNKT cell anergy, and Aim 3 will evaluate the long-term effects of iNKT cell unresponsiveness to the subsequent generation of iNKT cell-controlled immune responses. Completion of the work described in this proposal will provide novel insight into fundamental iNKT cell biology, the response of iNKT cells to glycolipid antigens, and the immunomodulatory activities of iNKT cells during health and disease. These proposed studies will build a foundation of knowledge on which safe and effective iNKT cell-based vaccines and therapies can be established. Relevance to Public Health: Studies proposed in this application will contribute significantly to the development of better preventive measures and therapies of infections, cancers, and autoimmune (e.g., type 1 diabetes, multiple sclerosis and lupus), allergic and inflammatory (e.g., atherosclerosis) diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070305-05
Application #
8110666
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Miller, Lara R
Project Start
2007-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$368,968
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
Van Kaer, Luc; Parekh, Vrajesh V; Postoak, J Luke et al. (2017) Role of autophagy in MHC class I-restricted antigen presentation. Mol Immunol :
Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M et al. (2017) Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective. Front Immunol 8:1858
Van Kaer, Luc; Wu, Lan; Joyce, Sebastian (2016) Mechanisms and Consequences of Antigen Presentation by CD1. Trends Immunol 37:738-754
Van Kaer, Luc (2015) Innate and virtual memory T cells in man. Eur J Immunol 45:1916-20
Van Kaer, Luc; Algood, Holly M Scott; Singh, Kshipra et al. (2014) CD8??? innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity 41:451-464
Wu, Lan; Parekh, Vrajesh V; Hsiao, Joseph et al. (2014) Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance. Proc Natl Acad Sci U S A 111:E4638-47
Van Kaer, Luc; Parekh, Vrajesh V; Wu, Lan (2013) Invariant natural killer T cells as sensors and managers of inflammation. Trends Immunol 34:50-8
Wu, Lan; Van Kaer, Luc (2013) Contribution of lipid-reactive natural killer T cells to obesity-associated inflammation and insulin resistance. Adipocyte 2:12-16
Parekh, Vrajesh V; Wu, Lan; Boyd, Kelli L et al. (2013) Impaired autophagy, defective T cell homeostasis, and a wasting syndrome in mice with a T cell-specific deletion of Vps34. J Immunol 190:5086-101
Andoh, Yasuhiro; Ogura, Hisako; Satoh, Masashi et al. (2013) Natural killer T cells are required for lipopolysaccharide-mediated enhancement of atherosclerosis in apolipoprotein E-deficient mice. Immunobiology 218:561-9

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