Abstract
Engagement of TCR by its ligand, the MHC/peptide complex, causes T cell activation. T cells respond positively to stimulation with agonists, and are inhibited by antagonist MHC/peptide ligands. Failure to induce proper conformational changes in the TCR or fast TCR/MHC dissociation are the leading models proposed to explain anergy induction by antagonist ligands. In this study, we demonstrate that presentation of between 1 and 10 complexes of agonist/MHC II by unfixed APC induces T cell anergy that persists up to 7 days and has characteristics similar to anergy induced by antagonist ligand or TCR occupancy without costimulation. Furthermore, anergy-inducing doses of hemagglutinin 306-318 peptide led to the engagement of less than 1000 TCR/CD3 complexes. Thus, engagement of a subthreshold number of TCR by either a low density of agonist/MHC or a 2-3 orders of magnitude higher density of antagonist/MHC causes anergy. Moreover, we show that anergy induced by low agonist concentrations is inhibited in the presence of IL-2 or cyclosporin A, suggesting involvement of the calcineurin signaling pathway.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Clonal Anergy / drug effects
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Clonal Anergy / immunology*
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Clone Cells
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Cyclosporine / pharmacology
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Cytokines / biosynthesis
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Dose-Response Relationship, Immunologic
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Down-Regulation / immunology
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HLA-DR1 Antigen / analysis
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Hemagglutinin Glycoproteins, Influenza Virus
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Hemagglutinins, Viral / analysis
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Hemagglutinins, Viral / immunology
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Hemagglutinins, Viral / pharmacology
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-2 / pharmacology
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Ligands
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Macromolecular Substances
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Orthomyxoviridae / immunology
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Peptide Fragments / analysis
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Peptide Fragments / immunology
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Peptide Fragments / pharmacology
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Receptors, Antigen, T-Cell / agonists*
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Receptors, Antigen, T-Cell / antagonists & inhibitors
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Receptors, Antigen, T-Cell / biosynthesis
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Interleukin-2 / biosynthesis
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T-Lymphocytes / chemistry
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism*
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Time Factors
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Up-Regulation / immunology
Substances
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Cytokines
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HLA-DR1 Antigen
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Hemagglutinin Glycoproteins, Influenza Virus
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Hemagglutinins, Viral
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Immunosuppressive Agents
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Interleukin-2
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Ligands
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Macromolecular Substances
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Peptide Fragments
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Receptors, Antigen, T-Cell
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Receptors, Interleukin-2
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influenza hemagglutinin (306-318)
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Cyclosporine