title: CTLA-4 regulates expansion and differentiation of Th1 cells following induction of peripheral T cell tolerance.
abstract: Intravenous treatment with Ag (peptide)-coupled, ethylene carbodiimide-fixed syngeneic splenocytes (Ag-SP) is a powerful method to induce anergy in vitro and peripheral T cell tolerance in vivo. In this study, we examined the effects of Ag-SP administration on T cell activity ex vivo and in vivo using OVA-specific DO11.10 TCR transgenic T cells. Although treatment with OVA323-339-SP resulted in a strong inhibition of peptide-specific T cell recall responses in vitro, examination of the immediate effects of Ag-SP treatment on T cells in vivo demonstrated that tolerogen injection resulted in rapid T cell activation and proliferation. Although there was an increase in the number of OVA-specific DO11.10 T cells detected in the lymphoid organs, these previously tolerized T cells were strongly inhibited in mounting proliferative or inflammatory responses upon rechallenge in vivo with peptide in CFA. This unresponsiveness was reversible by treatment with anti-CTLA-4 mAb. These results are consistent with the hypothesis that Ag-SP injection induces a state of T cell anergy that is maintained by CTLA-4 engagement.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Todd N
authors.initials: TN
authors.lastname: Eagar
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Turley
authors.forename: Josette
authors.initials: J
authors.lastname: Padilla
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: Litjen
authors.initials: L
authors.lastname: Tan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D001769:Blood / Q000276:immunology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation; D002455:Cell Division; D002645:Chickens; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin