Abstract
NKT cells in the mouse recognize antigen in the context of the MHC class I-like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases. NKT cells are usually activated by CD1d-presented lipid antigens. However, peptide recognition in the context of CD1 has also been documented, although no self-peptide ligands have been reported to date. Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells. This peptide, the immunodominant epitope from mouse collagen type II (mCII707-721), was not associated with either MHC class I or II. Activation of CD1d-restricted mCII707-721-specific NKT cells was induced via TCR signaling and classical costimulation. In addition, mCII707-721-specific NKT cells induced T cell death through Fas/FasL, in an IL-17A-independent fashion. Moreover, mCII707-721-specific NKT cells suppressed a range of in vivo inflammatory conditions, including delayed-type hypersensitivity, antigen-induced airway inflammation, collagen-induced arthritis, and EAE, which were all ameliorated by mCII707-721 vaccination. The findings presented here offer new insight into the intrinsic roles of NKT cells in health and disease. Given the results, endogenous collagen peptide activators of NKT cells may offer promise as novel therapeutics in tissue-specific autoimmune and inflammatory diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / immunology
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Animals
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Antigen Presentation
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Antigens, CD1d / genetics
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Antigens, CD1d / immunology*
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology
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Arthritis, Experimental / therapy
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Base Sequence
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CD4 Antigens / genetics
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CD4 Antigens / immunology
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CD8 Antigens / genetics
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CD8 Antigens / immunology
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Collagen Type II / administration & dosage
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Collagen Type II / immunology*
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DNA Primers / genetics
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / therapy
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Fas Ligand Protein / immunology
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Genes, MHC Class II
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Genes, T-Cell Receptor
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Hypersensitivity, Delayed / genetics
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Hypersensitivity, Delayed / immunology
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Hypersensitivity, Delayed / therapy
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Immunodominant Epitopes / administration & dosage
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Inflammation / genetics
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Inflammation / immunology*
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Inflammation / therapy*
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Natural Killer T-Cells / immunology*
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology*
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Respiratory Hypersensitivity / genetics
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Respiratory Hypersensitivity / immunology
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Respiratory Hypersensitivity / therapy
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Th1 Cells / immunology
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Th2 Cells / immunology
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Vaccination
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fas Receptor / immunology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters
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Antigens, CD1d
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CD4 Antigens
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CD8 Antigens
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Cd1d1 protein, mouse
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Collagen Type II
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DNA Primers
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Fas Ligand Protein
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Fas protein, mouse
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Fasl protein, mouse
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Immunodominant Epitopes
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Peptide Fragments
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Tap1 protein, mouse
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fas Receptor