Some T cells recognize lipid antigens presented by class I MHC-like CD1 molecules. Although self-lipid antigens activating them have not yet been identified, most NK T cells are thought to be autoreactive and can be rapidly activated by a surrogate glycolipid ligand alpha-galactosyl ceramide or alpha-GalCer. To characterize self-glycolipid-reactive T cells, their phenotype and their physiological function, we have focused on the recognition of a major myelin-derived glycolipid, sulfatide, (3'-sulfated beta-galactosyl ceramide). We have generated sulfatide-CD1d-tetramers and have identified sulfatide-reactive T cell populations in the liver, thymus and spleen from naive C57BL/6 mice. We have also generated sulfatide-reactive T cell hybridomas. During the course of antigen-induced experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) in humans, sulfatide-CD1d-tetramer+ T cells are selectively increased several-fold within the central nervous system. Treatment with sulfatide can both prevent and reverse ongoing EAE in wild type but not in CD1d-deficient mice. Based on our findings we propose that sulfatide is a self-glycolipid ligand recognized by a distinct population of CD1d-restricted T cells that can be activated to modulate autoimmune responses. We will use sulfatide- and a-GalCer-CD1d-tetramers and antibodies against various cell surface markers on NK T cells to characterize the phenotype of sulfatide-reactive T cells. Sulfatide-reactive T cell hybridomas will be used to analyze the antigen fine specificity and the TCR V-gene repertoire. Using glycolipid tetramers and Elispot analysis we will determine the dynamics of their activation and investigate mutual interactions among different lipid-reactive T cell populations. We will determine the number, phenotype and the fate of NK cells, B cells and myelin protein-reactive pathogenic CD4 T cells following sulfatide injection of wild type and CD1d-deficient mice. In adoptive transfer experiments we will directly examine the regulatory potential of sulfatide-CD ld-tetramer+ T cells. Neutralizing antibodies and mice genetically deficient for type 1 and 2 cytokines will be used to determine their role in the modulation of EAE by sulfatide. We will optimize treatment of ongoing disease with sulfatide in order to explore its therapeutic potential. These studies are important not only for understanding the biology of a naturally occurring self-glycolipid-reactive T cell population, but also because of the highly conserved nature of CD1d molecules across species they will form the basis for manipulation of human autoimmune demyelinating diseases, such as MS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100660-04
Application #
7226324
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$353,768
Indirect Cost
Name
Torrey Pines Institute for Molecular Studies
Department
Type
DUNS #
605758754
City
Port Saint Lucie
State
FL
Country
United States
Zip Code
34987
Dhodapkar, Madhav V; Kumar, Vipin (2017) Type II NKT Cells and Their Emerging Role in Health and Disease. J Immunol 198:1015-1021
Mathews, Stephanie; Feng, Dechun; Maricic, Igor et al. (2016) Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol 13:206-16
Marrero, Idania; Aguilera, Carlos; Hamm, David E et al. (2016) High-throughput sequencing reveals restricted TCR V? usage and public TCR? clonotypes among pancreatic lymph node memory CD4(+) T cells and their involvement in autoimmune diabetes. Mol Immunol 74:82-95
Bandyopadhyay, Keya; Marrero, Idania; Kumar, Vipin (2016) NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol 13:337-46
Maricic, Igor; Sheng, Huiming; Marrero, Idania et al. (2015) Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 61:1357-69
Maricic, Igor; Girardi, Enrico; Zajonc, Dirk M et al. (2014) Recognition of lysophosphatidylcholine by type II NKT cells and protection from an inflammatory liver disease. J Immunol 193:4580-9
Kumar, Vipin; Delovitch, Terry L (2014) Different subsets of natural killer T cells may vary in their roles in health and disease. Immunology 142:321-36
Maricic, Igor; Halder, Ramesh; Bischof, Felix et al. (2014) Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis. J Immunol 193:1035-46
Kumar, Vipin (2013) NKT-cell subsets: promoters and protectors in inflammatory liver disease. J Hepatol 59:618-20
Girardi, Enrico; Maricic, Igor; Wang, Jing et al. (2012) Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol 13:851-6

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