Human CD8 responses to a complete epitope set from preproinsulin: implications for approaches to epitope discovery

Caroline Baker, Liliana G Petrich de Marquesini, Amanda J Bishop, Alan J Hedges, Colin M Dayan, F Susan Wong, Caroline Pope

Research output: Contribution to journalArticle (Academic Journal)peer-review

19 Citations (Scopus)

Abstract

PURPOSE: In this study, we explored the breadth of CD8 T cell reactivity to preproinsulin (PPI) in type 1 diabetes.

MATERIALS AND METHODS: We tested a complete peptide set in pools covering all 406 potential 8-11mer epitopes of PPI and 61 algorithm-predicted human leukocyte antigen (HLA)-A2-specific epitopes (15 pools) from islet-specific glucose-6-phophatase catalytic subunit-related protein (IGRP), using a CD8-specific granzyme B enzyme-linked immunosorbent spot assay.

RESULTS: Responses were seen to 64 of the 102 PPI pools in two or more newly diagnosed patients (63%) compared to 11 pools in the control subjects (11%, p < 0.0001, Fisher's exact test). We identified five pools containing 20 peptides, which distinguished patients from control subjects, most of which had predicted low-affinity binding to HLA class I molecules. In contrast, fewer (5 of 15 = 33%) IGRP peptide pools, selected by higher binding affinity for HLA-A2 (present in seven of eight patients and five of seven control subjects), stimulated responses in two or more patients, and none stimulated responses in more than two control subjects (p = 0.042, Fisher's exact test).

CONCLUSION: Thus, we conclude that CD8 T cell reactivity to PPI in patients with type 1 diabetes can be much broader than shown previously and more diverse than seen in control subjects. Furthermore, responses were often stimulated by peptides with low predicted HLA-binding affinities.

Translated title of the contributionHuman CD8 responses to a complete epitope set from preproinsulin: implications for approaches to epitope discovery
Original languageEnglish
Pages (from-to)350-360
Number of pages11
JournalJournal of Clinical Immunology
Volume28
Issue number4
DOIs
Publication statusPublished - Jul 2008

Keywords

  • Adult
  • Autoantibodies
  • Autoantigens
  • CD8-Positive T-Lymphocytes
  • Diabetes Mellitus, Type 1
  • Epitopes, T-Lymphocyte
  • Female
  • Glucose-6-Phosphatase
  • Glutamate Decarboxylase
  • Granzymes
  • Humans
  • Insulin
  • Lymphocyte Activation
  • Male
  • Peptide Library
  • Protein Precursors

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