Characterization of immune response to novel HLA-A2-restricted epitopes from zinc transporter 8 in type 1 diabetes |
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| Institution: | 1. Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China;2. INSERM, U1016, Cochin Institute, Paris, France;3. CNRS, UMR8104, Cochin Institute, Paris, France;4. Paris Descartes University, Sorbonne Paris Cité, Paris, France;5. Assistance Publique Hôpitaux de Paris, Dept. of Diabetology, Cochin Hospital, Paris, France;6. Department of Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, USA;7. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA;1. Medical Oncology Unit, Department of Oncology, Ospedale San Donato, Istituto Toscano Tumori (ITT), Arezzo, Italy;2. Medical Oncology and Immunotherapy Unit, Azienda Ospedaliera Senese, University of Siena, Istituto Toscano Tumori (ITT), Siena, Italy;1. Frontage Clinical Research Center, 241 Main Street, 3rd Floor, Hackensack, NJ 07601, USA;2. Pfizer Vaccine Research, 500 Arcola Rd, Collegeville, PA 19426, USA;3. Pfizer Vaccine Research, 401 N Middletown Rd , Pearl River, NY 10965, USA;4. Pfizer Medical and Scientific Affairs, 500 Arcola Rd, Collegeville, PA 19426, USA;1. Centro de Investigación en Sanidad Animal, INIA-CISA, Valdeolmos, 28130 Madrid, Spain;2. The Pirbright Institute, Ash Road, Pirbright, Surrey GU24 0NF, UK |
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| Abstract: | ObjectiveZnT8-specific CD8+ T cells in human type 1 diabetes (T1D) have been reported recently, although the results from different laboratories are inconsistent. We aimed to characterize these ZnT8 specific CD8+ T cells and validate assays to screen peptide libraries.MethodsWe screened HLA-A2-restricted T cell candidate peptides of ZnT8 with different methods including computer algorithms, MHC-peptide binding and dissociation assays in T2 cell line, identification in HLA-A2 transgenic (Tg) mice and in vivo CTL assays. Then ELISpot assay was used to measure peptide-reactive T cell responses in 49 HLA-A2-restricted T1D patients.ResultsWe demonstrated that ZnT8107–116(115), ZnT8110–118, and ZnT8177–186 were novel HLA-A*0201-restricted CTL epitopes in T1D patients. ZnT8107–116(115), ZnT8115–123, ZnT8153–161, ZnT8177–186 and ZnT8291–300 represent potentially major biomarkers for T1D. T cell responses against these epitopes showed different distributions between recently diagnosed and long-standing patients. Furthermore, they displayed discriminating performance among different ethnicities. We also compared the performance of the epitope identification strategies used herein. The epitopes which exhibited strong immunogenicity in HLA-A2 Tg mice were also well recognized by T1D patients.ConclusionsThe differences in autoimmune T cell responses among T1D individuals may open new avenues toward T1D prediction and prevention. It also provides efficient strategies for immune intervention. |
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| Keywords: | Autoimmune disease Diabetes T lymphocytes Epitope |
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