Zinc transporter (ZnT)8186–194 is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients

Inserm, U986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France.
Diabetologia (Impact Factor: 6.67). 04/2012; 55(7):2026-31. DOI: 10.1007/s00125-012-2543-z
Source: PubMed


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.
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.
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)).
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.

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Available from: Leonardo A Sechi
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    • "Since the autoimmune cascade leading to beta cell destruction in T1DM is propagated by T cell recognition of specific epitopes, epitope mapping may be critical for staging of autoimmunity during the disease, as well as for developing and monitoring immunomodulatory therapies . Thus, exploring T cell epitopes in ZnT8 revealed that ZnT8 (186-194) is an immunodominant CD8+ T cell epitope (60-85% of patients) and ZnT8 (153-161) is a second rank epitope (20-25% of patients) in HLA-A2+ T1DM patients [50]. Another study further confirmed that ZnT8 (153-161) is a CD8+ T cell epitope in human T1DM [51]. "
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is characterized by recognition of beta cell proteins as self-antigens, called autoantigens (AAgs), by patients' own CD4+ and CD8+ T cells and/or the products of self-reactive B cells, called autoantibodies. These AAgs are divided into two categories on the basis of beta-cell-specificity. The list of the targets associated with beta cell-specific AAgs is continuously growing. Many T1DM-associated AAgs are well characterized and have important clinical applications for disease prediction, diagnosis, and antigen-specific tolerance immunotherapy. Identification of T1DM-associated AAgs provides insight into the pathogenesis of T1DM and to understanding the clinical aspects of the disease. Since many excellent reviews have covered the previously identified T1DM-associated AAgs exhaustedly, here we only focus on several recently discovered T1DM-AAgs (PDX1, ZnT8, CHGA, and IAAP).
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    • "Interestingly, ZnT8-reactive CD8+ T cells are also predominantly directed against the ZnT8186–194 epitope and are detected in a majority of T1D patients outside Sardinia [13]. Indeed, Scotto et al. recently described that 60% of white HLA-A2(+) new T1D onset children, displayed ZnT8-reactive CD8(+) T cells capable of recognizing ZnT8186–194. "
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