title: Characterization of immune response to novel HLA-A2-restricted epitopes from zinc transporter 8 in type 1 diabetes.
abstract: OBJECTIVE
  ZnT8-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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We demonstrated that ZnT8(107-116)(115), ZnT8(110-118), and ZnT8(177-186) were novel HLA-A*0201-restricted CTL epitopes in T1D patients. ZnT8(107-116)(115), ZnT8(115-123), ZnT8(153-161), ZnT8(177-186) and ZnT8(291-300) 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Bian
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Kuanfeng
authors.initials: K
authors.lastname: Xu
authors.affiliation: INSERM, U1016, Cochin Institute, Paris, France; CNRS, UMR8104, Cochin Institute, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France; Assistance Publique Hôpitaux de Paris, Dept. of Diabetology, Cochin Hospital, Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.affiliation: Department of Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, USA.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Davidson
authors.affiliation: Department of Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China; Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jinxiong
authors.initials: J
authors.lastname: She
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China. Electronic address: zhangmei@njmu.edu.cn.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D044466:Asian People; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D019151:Peptide Library; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D044465:White People; D055815:Young Adult; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D019151:Peptide Library; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8
keywords: Autoimmune disease; Diabetes; Epitope; T lymphocytes