Abstract
In vivo models have shown that tissue-restricted antigen may be captured by bone marrow-derived cells and cross-presented for the tolerization of CD8+ T cells. Although these studies have shown peripheral tolerization of CD8+ T cells, the mechanism of antigen transfer and the nature of the antigen-presenting cell (APC) remain undefined. We report here the establishment of an in vitro system for the study of cross-tolerance and show that dendritic cells (DCs) phagocytose apoptotic cells and tolerize antigen-specific CD8+ T cells when cognate CD4+ T helper cells are absent. Using this system, we directly tested the "two-signal" hypothesis for the regulation of priming versus tolerance. We found that the same CD83+ myeloid-derived DCs were required for both cross-priming and cross-tolerance. These data suggested that the current model for peripheral T cell tolerance, "signal 1 in the absence of signal 2", requires refinement: the critical checkpoint is not DC maturation, but instead the presence of a third signal, which is active at the DC-CD4+ T cell interface.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Antigen Presentation
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Antigens, CD
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Antigens, Differentiation / pharmacology
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Antigens, Viral / immunology
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Apoptosis
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CD28 Antigens / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD40 Antigens / immunology
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CD40 Ligand / immunology
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CD8-Positive T-Lymphocytes / immunology*
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CD83 Antigen
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CTLA-4 Antigen
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Cell Communication
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Cell Differentiation
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Cells, Cultured
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Coculture Techniques
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Cross-Over Studies
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Culture Media, Conditioned / chemistry
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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HLA-DR Antigens / immunology
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Humans
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Immune Tolerance / immunology*
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Immunoconjugates*
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Immunoglobulins / immunology
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Interleukin-1 / pharmacology
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Interleukin-12 / analysis
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Interleukin-12 / pharmacology
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins / immunology
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Models, Immunological*
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Orthomyxoviridae / immunology
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Phagocytosis
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Signal Transduction
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Tumor Necrosis Factor-alpha / analysis
Substances
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Antigens, CD
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Antigens, Differentiation
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Antigens, Viral
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CD28 Antigens
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CD40 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Culture Media, Conditioned
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HLA-DR Antigens
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Immunoconjugates
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Immunoglobulins
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Interleukin-1
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Membrane Glycoproteins
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Tumor Necrosis Factor-alpha
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CD40 Ligand
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Interleukin-12
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Abatacept