title: The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance.
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.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Todd N
authors.initials: TN
authors.lastname: Eagar
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D002478:Cells, Cultured / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance; D007114:Immunization; D018796:Immunoconjugates; D007249:Inflammation; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013934:Thymectomy
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D036022:Capsid Proteins; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; C111390:OVA 323-339; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C094241:myelin basic protein 84-104; C435023:myelin proteolipid protein (139-151); C094242:myelin proteolipid protein (178-191); D000069594:Abatacept; D010047:Ovalbumin