title: CTLA-4 is required for the induction of high dose oral tolerance.
abstract: Mucosal and systemic administrations of high dose antigens induce long-lasting peripheral T cell tolerance. We and others have shown that high dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the present study, we examined the roles of the B7 co-stimulation pathway in the generation of high dose peripheral T cell tolerance. We found that blocking B7:CD28/CTLA-4 interaction at the time of tolerance induction partially prevented T cell tolerance, whereas selective blockade of B7:CTLA-4 interaction completely abrogated peripheral T cell tolerance induced by either oral or i.p. antigens. These results suggest that CTLA-4-mediated feedback regulation plays a crucial role in the induction of high dose peripheral T cell tolerance.
authors.affiliation: Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Samoilova
authors.forename: J L
authors.initials: JL
authors.lastname: Horton
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: S J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: H L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000069594:Abatacept; D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D004305:Dose-Response Relationship, Drug; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept