Characterization of immune response to novel HLA-A2-restricted epitopes from zinc transporter 8 in type 1 diabetes

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• 作者：Xinyu Xu^a ; ¹ ; Yong Gu^a ; ¹ ; Lingling Bian^a ; Yun Shi^a ; Yun Cai^a ; Yang Chen^a ; Heng Chen^a ; Li Qian^a ; Xiangmei Wu^a ; Kuanfeng Xu^a ; Roberto Mallone^b ; ^c ; ^d ; ^e ; Howard W. Davidson^f ; Liping Yu^f ; Jinxiong She^a ; ^g ; Mei Zhang^a ; ^{zhangmei@njmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Tao Yang^a
• 关键词：Tg ; transgenic ; ZnT8 ; zinc transporter-8 ; CTL ; cytotoxic lymphocyte ; GAD65 ; glutamic acid decarboxylase ; IA-2 ; tyrosine phosphatase-related islet antigen 2 ; DMSO ; dimethyl sulphoxide ; CMV ; cytomegalovirus ; PBMCs ; peripheral blood mononuclear cells ; CFSE ; carboxyfluorescein diacetate succinimidyl ester ; HLA ; human leukocyte antigen
• 刊名：Vaccine
• 出版年：2016
• 出版时间：3 February 2016
• 年：2016
• 卷：34
• 期：6
• 页码：854-862
• 全文大小：2399 K

文摘

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.