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

Vaccine. 2016 Feb 3;34(6):854-62. doi: 10.1016/j.vaccine.2015.10.108. Epub 2015 Nov 3.

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.

Keywords: Autoimmune disease; Diabetes; Epitope; T lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Asian Continental Ancestry Group
  • CD8-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Cation Transport Proteins / immunology*
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme-Linked Immunospot Assay
  • Epitopes, T-Lymphocyte / immunology*
  • European Continental Ancestry Group
  • Female
  • HLA-A2 Antigen / genetics*
  • Humans
  • Male
  • Mice, Transgenic
  • Middle Aged
  • Peptide Library
  • T-Lymphocytes, Cytotoxic / immunology
  • Young Adult
  • Zinc Transporter 8

Substances

  • Cation Transport Proteins
  • Epitopes, T-Lymphocyte
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Peptide Library
  • SLC30A8 protein, human
  • Zinc Transporter 8