title: Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes.
abstract: Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4(+) T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLA-matched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Vimukthi
authors.initials: V
authors.lastname: Pathiraja
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Janine P
authors.initials: JP
authors.lastname: Kuehlich
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Campbell
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Loudovaris
authors.affiliation: Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: P Toby H
authors.initials: PT
authors.lastname: Coates
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Brodnicki
authors.affiliation: National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.affiliation: University of Melbourne, NorthWest Academic Centre, Sunshine Hospital, St. Albans, Victoria, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Rodda
authors.affiliation: Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Erin
authors.initials: E
authors.lastname: Hill
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia smannering@svi.edu.au.
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Mannering
mesh_terms: D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D019281:Dimerization; D018604:Epitope Mapping; D006682:HLA-DP Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D011384:Proinsulin / Q000276:immunology*
chemical_list: D006682:HLA-DP Antigens; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D006684:HLA-DR Antigens; D011384:Proinsulin