title: Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.
abstract: OBJECTIVE
  Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets.
  
  
  METHODS
  Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot.
  
  
  RESULTS
  White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)).
  
  
  CONCLUSIONS
  ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.
authors.affiliation: Inserm, U986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France.
authors.forename: M
authors.initials: M
authors.lastname: Scotto
authors.forename: G
authors.initials: G
authors.lastname: Afonso
authors.forename: E
authors.initials: E
authors.lastname: Larger
authors.forename: C
authors.initials: C
authors.lastname: Raverdy
authors.forename: F A
authors.initials: FA
authors.lastname: Lemonnier
authors.forename: J C
authors.initials: JC
authors.lastname: Carel
authors.forename: D
authors.initials: D
authors.lastname: Dubois-Laforgue
authors.forename: B
authors.initials: B
authors.lastname: Baz
authors.forename: D
authors.initials: D
authors.lastname: Levy
authors.forename: J F
authors.initials: JF
authors.lastname: Gautier
authors.forename: O
authors.initials: O
authors.lastname: Launay
authors.forename: G
authors.initials: G
authors.lastname: Bruno
authors.forename: C
authors.initials: C
authors.lastname: Boitard
authors.forename: L A
authors.initials: LA
authors.lastname: Sechi
authors.forename: J C
authors.initials: JC
authors.lastname: Hutton
authors.forename: H W
authors.initials: HW
authors.lastname: Davidson
authors.forename: R
authors.initials: R
authors.lastname: Mallone
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8