Prediction of HLA class I-restricted T-cell epitopes of islet autoantigen combined with binding and dissociation assays

被引:18
|
作者
Wu, Xiangmei [1 ]
Xu, Xinyu [1 ]
Gu, Rong [1 ]
Wang, Zhixiao [1 ]
Chen, Heng [1 ]
Xu, Kuanfeng [1 ]
Zhang, Mei [1 ]
Hutton, John [2 ,3 ]
Yang, Tao [1 ]
机构
[1] Nanjing Med Univ, Dept Endocrinol, Affiliated Hosp 1, Nanjing 210029, Jiangsu, Peoples R China
[2] Univ Colorado Denver, Dept Barbara Davis Ctr Childhood Diabet, Denver, CO USA
[3] Univ Colorado, Hlth Sci Ctr, Denver, CO USA
基金
中国国家自然科学基金;
关键词
T-cell epitope; type; 1; diabetes; ZnT8; autoantigen; autoimmunity; GENOME-WIDE ASSOCIATION; PEPTIDE; IDENTIFICATION; IMMUNOGENICITY; RESPONSES; PREPROINSULIN; AUTOIMMUNITY; AFFINITY; INSULIN; COMPLEX;
D O I
10.3109/08916934.2011.622014
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Identification of cognate peptides recognized by human leucocyte antigen (HLA)/T cell receptor (TCR) complex provides insight into the pathogenic process of type 1 diabetes (T1D). We hypothesize that HLA-binding assays alone are inadequate metrics for the affinity of peptides. Zinc transporter-8 (ZnT8) has emerged in recent years as a novel, major, human autoantigen. Therefore, we aim to identify the HLA-A2-restricted ZnT8 epitopes using both binding and dissociation assays. HLA class I peptide affinity algorithms were used to predict candidate ZnT8 peptides that bind to HLA-A2. We analyzed 15 reported epitopes of seven beta-cell candidate autoantigens and eight predicted candidate ZnT8 peptides using binding and dissociation assays. Using IFN-gamma ELISpot assay, we tested peripheral blood mononuclear cells (PBMCs) from recent-onset T1D patients and healthy controls for reactivity to seven reported epitopes and eight candidate ZnT8 peptides directly ex vivo. We found five of seven recently reported epitopes in Chinese T1D patients. Of the eight predicted ZnT8 peptides, ZnT8(153-161) had a strong binding affinity and the lowest dissociation rate to HLA-A(star)0201. We identified it as a novel HLA-A(star)0201-restricted T-cell epitope in three of eight T1D patients. We conclude that ZnT8(153-161) is a novel HLA-A(star)0201-restricted T-cell epitope. We did not observe a significant correlation (P = 0.3, R = -0.5) between cytotoxic T cell (CTL) response and peptide/HLA(star)0201 complex stability. However, selection of peptides based on affinity and their dissociation rate may be helpful for the identification of candidate CTL epitopes. Thus, we can minimize the number of experiments for the identification of T-cell epitopes from interesting antigens.
引用
收藏
页码:176 / 185
页数:10
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