title: Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice.
abstract: Tolerance to peripheral antigens is thought to result from the inability of parenchymal tissue to stimulate T cells--an inability that is believed to relate to the lack of expression of the costimulatory signal(s) required for T-cell activation. To test this model, we generated transgenic mice expressing costimulatory molecule B7-1 on the B cells of the pancreas. We find that islets from these transgenic mice are immunogenic for naive T cells in vitro and in vivo. Nonetheless, mice expressing the costimulator B7-1 specifically on beta cells do not develop diabetes, suggesting that expression of the B7-1 costimulator is not sufficient to abrogate the tolerance to peripheral antigens. We have reported that tumor necrosis factor alpha subunit (TNF-alpha) expressed by beta cells leads to a local inflammation but no islet destruction. Strikingly, however, the combination of a local inflammation due to the expression of the cytokine TNF-alpha and the expression of B7-1 results in tissue destruction and diabetes.
authors.affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: S
authors.initials: S
authors.lastname: Guerder
authors.forename: D E
authors.initials: DE
authors.lastname: Picarella
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015551:Autoimmunity; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D014409:Tumor Necrosis Factor-alpha