title: Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion.
abstract: T cell-mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. thomas.delong@ucdenver.edu katie.haskins@ucdenver.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Delong
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Wiles
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Rocky L
authors.initials: RL
authors.lastname: Baker
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Bradley
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Barbour
authors.affiliation: Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Reisdorph
authors.affiliation: Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Armstrong
authors.affiliation: Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Powell
authors.affiliation: Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
authors.forename: Nitesh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Elso
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: DeNicola
authors.affiliation: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. VA Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Sally C
authors.initials: SC
authors.lastname: Kent
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Mannering
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. thomas.delong@ucdenver.edu katie.haskins@ucdenver.edu.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haskins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002096:C-Peptide / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D000939:Epitopes / Q000276:immunology*; D007108:Immune Tolerance; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology
chemical_list: D002096:C-Peptide; D000939:Epitopes; D010455:Peptides