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Journal of Virology, December 2004, p. 13399-13408, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13399-13408.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of a Naturally Processed Cytotoxic CD8 T-Cell Epitope of Coxsackievirus B4, Presented by HLA-A2.1 and Located in the PEVKEK Region of the P2C Nonstructural Protein

Department of Immunobiology, GKT School of Medicine, Guy's Hospital, London, United Kingdom

Received 8 October 2003/ Accepted 3 August 2004

The adaptive immune system generates CD8 cytotoxic T lymphocytes (CTLs) as a major component of the protective response against viruses. Knowledge regarding the nature of the peptide sequences presented by HLA class I molecules and recognized by CTLs is thus important for understanding host-pathogen interactions. In this study, we focused on identification of a CTL epitope generated from coxsackievirus B4 (CVB4), a member of the enterovirus group responsible for several inflammatory diseases in humans and often implicated in the triggering and/or acceleration of the autoimmune disease type 1 diabetes. We identified a 9-mer peptide epitope that can be generated from the P2C nonstructural protein of CVB4 (P2C_1137-1145) and from whole virus by antigen-presenting cells and presented by HLA-A2.1. This epitope is recognized by effector memory (gamma interferon [IFN-]-producing) CD8 T cells in the peripheral blood at a frequency of responders that suggests that it is a major focus of the anti-CVB4 response. Short-term CD8 T-cell lines generated against P2C_1137-1145 are cytotoxic against peptide-loaded target cells. Of particular interest, the epitope lies within a region of viral homology with the diabetes-related autoantigen, glutamic acid decarboxylase-65 (GAD₆₅). However, P2C_1137-1145-specific cytotoxic T lymphocyte (CTL) lines were not activated to produce IFN- by the GAD₆₅ peptide homologue and did not show cytotoxic activity in the presence of appropriately labeled targets. These results describe the first CD8 T-cell epitope of CVB4 that will prove useful in the study of CVB4-associated disease.

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