title: Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes.
abstract: Type 1 diabetes results from chronic autoimmune destruction of insulin-producing β-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Michels
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Landry
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: McDaniel
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA.|Department of Medicine, University of Washington, Seattle, WA.
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.affiliation: Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.|Howard Hughes Medical Institute, Denver, CO.|Department of Biomedical Research, National Jewish Health, Denver, CO.|Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA.|Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.|Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO maki.nakayama@ucdenver.edu.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000293:Adolescent; D001324:Autoantigens / Q000276:immunology*; D002096:C-Peptide / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000276:immunology*; D050417:Insulin-Secreting Cells; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology*; D011384:Proinsulin / Q000276:immunology*; D011498:Protein Precursors / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; D002096:C-Peptide; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; C097877:insulin B (9-23); C013737:preproinsulin; D011384:Proinsulin