Date: 29 Feb 2008
Human CD8 Responses to a Complete Epitope Set from Preproinsulin: Implications for Approaches to Epitope Discovery
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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.
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).
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.
Martinez NR, Augstein P, Moustakas AK, Papadopoulos GK, Gregori S, Adorini L, et al. Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest 2003;111:1365–71.PubMed
Wong CP, Li L, Frelinger JA, Tisch R. Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic nonobese diabetic mice. J Immunol 2006;176:1637–44.PubMed
Takaki T, Marron MP, Mathews CE, Guttmann ST, Bottino R, Trucco M, et al. HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 2006;176:3257–65.PubMed
Olcott AP, Tian J, Walker V, Dang H, Middleton B, Adorini L, et al. Antigen-based therapies using ignored determinants of beta cell antigens can more effectively inhibit late-stage autoimmune disease in diabetes-prone mice. J Immunol 2005;175:1991–9.PubMed
Blancou P, Mallone R, Martinuzzi E, Severe S, Pogu S, Novelli G, et al. Immunization of HLA class I transgenic mice identifies autoantigenic epitopes eliciting dominant responses in type 1 diabetes patients. J Immunol 2007;178:7458–66.PubMed
Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004;113:451–63.PubMed
- Human CD8 Responses to a Complete Epitope Set from Preproinsulin: Implications for Approaches to Epitope Discovery
Journal of Clinical Immunology
Volume 28, Issue 4 , pp 350-360
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
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- Type 1 diabetes
- CD8 T cells
- Industry Sectors
- Author Affiliations
- 1. Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK
- 2. Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK