title: Increased endogenous antigen presentation in the periphery enhances susceptibility to inflammation-induced gastric autoimmunity in mice.
abstract: How the immune system maintains peripheral tolerance under inflammatory conditions is poorly understood. Here we assessed the fate of gastritogenic T cells following inflammatory activation in vivo. Self-reactive T cells (A23 T cells) specific for the gastric H+/K+ATPase α subunit (HKα) were transferred into immunosufficient recipient mice and immunised at a site distant to the stomach with adjuvant containing the cognate HKα peptide antigen. Activation of A23 T cells by immunisation did not impact on either immune tolerance or protection from gastric autoimmunity in wild-type BALB/c mice. However, increased presentation of endogenously derived HKα epitopes by dendritic cells (DCs) in the gastric lymph node of IE-H+/K+β transgenic mice (IEβ) reduces A23 T-cell tolerance to gastric antigens after inflammatory activation, with subsequent development of gastritis. While HKα-specific A23 T cells from immunised wild-type mice were poorly responsive to in vitro antigen specific activation, A23 T cells from immunised IEβ transgenic mice were readily re-activated, indicating loss of T-cell anergy. These findings show that DCs of gastric lymph nodes can maintain tolerance of pathogenic T cells following inflammatory stimulation and that the density of endogenous antigen presented to self-reactive T cells is critical in the balance between tolerance and autoimmunity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Overall
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Bourges
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia.
authors.forename: Ian R
authors.initials: IR
authors.lastname: van Driel
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Melbourne, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gleeson
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005756:Gastritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D015415:Biomarkers; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017506:H(+)-K(+)-Exchanging ATPase
keywords: Anergy; Antigen presentation; Autoimmune gastritis; Autoimmunity; Immunisation; Paragastric lymph node; Peripheral tolerance