title: ZnT8-reactive T cells are weakly pathogenic in NOD mice but can participate in diabetes under inflammatory conditions.
abstract: Autoantibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified in patients with type 1 diabetes. Here we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse. Immunization with a cytoplasmic domain of the protein or with peptides predicted to bind to I-A(g7) resulted in a CD4 T-cell response, indicating a lack of deletional tolerance. However, presentation by intraislet antigen-presenting cells (APC) to the T cells was not detectable in prediabetic mice. Presentation by islet APC was found only in islets of mice with active diabetes. In accordance, a culture assay indicated the weak transfer of ZnT8 reactivity from insulinomas or primary β-cells to APC for presentation to T cells. A T cell directed to one peptide (345-359) resulted in the transfer of diabetes, but only in conditions in which the recipient NOD mice or NOD.Rag1(-/-) mice were subjected to light irradiation. In late diabetic NOD mice, CD4 T cells were found as well as a weak antibody response. We conclude that in NOD mice, ZnT8 is a minor diabetogenic antigen that can participate in diabetes in conditions in which the islet is first made receptive to immunological insults.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Nayak
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Boris
authors.initials: B
authors.lastname: Calderon
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Vomund
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO unanue@wustl.edu.
authors.forename: Emil R
authors.initials: ER
authors.lastname: Unanue
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8