Abstract
MHC class I-mediated cross-priming of CD8 T cells by APCs is critical for CTL-based immunity to viral infections and tumors. We have shown previously that tumor-secreted heat shock protein gp96-chaperoned peptides cross prime CD8 CTL that are specific for genuine tumor Ags and for the surrogate Ag OVA. We now show that tumor-secreted heat shock protein gp96-chaperoned peptides enhance the efficiency of Ag cross-priming of CD8 CTL by several million-fold over the cross-priming activity of unchaperoned protein alone. Gp96 also acts as adjuvant for cross-priming by unchaperoned proteins, but in this capacity gp96 is 1000-fold less active than as a peptide chaperone. Mechanistically, the in situ secretion of gp96-Ig by transfected tumor cells recruits and activates dendritic cells and NK cells to the site of gp96 release and promotes CD8 CTL expansion locally. Gp96-mediated cross-priming of CD8 T cells requires B7.1/2 costimulation but proceeds unimpeded in lymph node-deficient mice, in the absence of NKT and CD4 cells and without CD40L. Gp96-driven MHC I cross-priming of CD8 CTL in the absence of lymph nodes provides a novel mechanism for local, tissue-based CTL generation at the site of gp96 release. This pathway may constitute a critically important, early detection, and rapid response mechanism that is operative in parenchymal tissues for effective defense against tissue damaging antigenic agents.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adjuvants, Immunologic* / genetics
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Adjuvants, Immunologic* / metabolism
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Animals
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Antigen Presentation / genetics
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Antigen Presentation / immunology*
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / metabolism
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B7-1 Antigen / genetics
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B7-1 Antigen / immunology
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B7-1 Antigen / metabolism
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B7-2 Antigen / genetics
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B7-2 Antigen / immunology
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B7-2 Antigen / metabolism
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CD4 Antigens / genetics
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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CD40 Ligand / deficiency
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CD40 Ligand / immunology
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CD40 Ligand / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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Cell Line, Tumor
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Cross Reactions / genetics
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Cross Reactions / immunology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / metabolism
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphoma / genetics
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Lymphoma / immunology*
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Lymphoma / metabolism
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Lymphoma / pathology
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Mice
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Mice, Knockout
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Organ Specificity / genetics
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Organ Specificity / immunology
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Peptides / genetics
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Peptides / immunology
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Peptides / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Transfection
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Virus Diseases / genetics
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Virus Diseases / immunology
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Virus Diseases / metabolism
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Virus Diseases / pathology
Substances
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Adjuvants, Immunologic
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Antigens, Neoplasm
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B7-1 Antigen
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B7-2 Antigen
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CD4 Antigens
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Cd86 protein, mouse
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Histocompatibility Antigens Class I
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Peptides
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Recombinant Fusion Proteins
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sarcoma glycoprotein gp96 rejection antigens
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CD40 Ligand