, Volume 55, Issue 7, pp 2026-2031

Zinc transporter (ZnT)8186–194 is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients

Abstract

Aims/hypothesis

Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8+ T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets.

Methods

Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot.

Results

White HLA-A2+ adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8+ T cells that recognised a single ZnT8186–194 (VAANIVLTV) epitope. This ZnT8186–194-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8+ T cells. Another sequence, ZnT8153–161 (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8186–194, 0% for ZnT8153–161).

Conclusions/interpretation

ZnT8-reactive CD8+ T cells are predominantly directed against the ZnT8186–194 epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8186–194 may point to common environmental triggers precipitating beta cell autoimmunity.

M. Scotto and G. Afonso contributed equally to this work.