title: Role of antigen-presenting cells in mediating tolerance and autoimmunity.
abstract: The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic beta-islet cells together with T cells expressing an LCMV-gp-specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.
authors.affiliation: Departments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Garza
authors.forename: S M
authors.initials: SM
authors.lastname: Chan
authors.forename: R
authors.initials: R
authors.lastname: Suri
authors.forename: L T
authors.initials: LT
authors.lastname: Nguyen
authors.forename: B
authors.initials: B
authors.lastname: Odermatt
authors.forename: S P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000956:Antigens, Viral; D015551:Autoimmunity / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins
chemical_list: D000956:Antigens, Viral; D018106:CD28 Antigens; D019013:CD40 Antigens; D006023:Glycoproteins; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D007371:Interferon-gamma