Abstract
T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Amino Acid Sequence
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Animals
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Antigens, CD / immunology
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Antigens, Differentiation / administration & dosage
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Antigens, Differentiation / immunology*
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Antigens, Differentiation / pharmacology
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Autoantigens / administration & dosage
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Autoantigens / immunology
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Autoimmune Diseases / immunology
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Autoimmune Diseases / therapy
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B7-1 Antigen / immunology
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B7-2 Antigen
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CTLA-4 Antigen
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Capsid / immunology
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Capsid Proteins
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Cells, Cultured / immunology
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Clonal Anergy / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / therapy
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Female
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Hypersensitivity, Delayed / immunology
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Immune Tolerance*
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Immunization
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Immunoconjugates*
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Inflammation
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Lymphocyte Activation
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Membrane Glycoproteins / immunology
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Mice
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Mice, Mutant Strains
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Molecular Sequence Data
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Myelin Basic Protein / immunology
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Myelin Proteolipid Protein / administration & dosage
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Myelin Proteolipid Protein / immunology
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Ovalbumin / immunology
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology
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Receptors, Antigen, T-Cell / immunology
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Specific Pathogen-Free Organisms
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T-Lymphocyte Subsets / immunology*
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Thymectomy
Substances
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Antigens, CD
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Antigens, Differentiation
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Autoantigens
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B7-1 Antigen
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B7-2 Antigen
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CTLA-4 Antigen
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Capsid Proteins
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Cd86 protein, mouse
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Ctla4 protein, mouse
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Immunoconjugates
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Membrane Glycoproteins
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Myelin Basic Protein
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Myelin Proteolipid Protein
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OVA 323-339
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Peptide Fragments
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Receptors, Antigen, T-Cell
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myelin basic protein 84-104
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myelin proteolipid protein (139-151)
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myelin proteolipid protein (178-191)
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Abatacept
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Ovalbumin