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.
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-gamma]-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 (GAD(65)). However, P2C(1137-1145)-specific cytotoxic T lymphocyte (CTL) lines were not activated to produce IFN-gamma by the GAD(65) 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.
Varela-Calvino
Ruben
R
Department of Immunobiology, GKT School of Medicine, 2nd Floor, New Guy's House, Guy's Hospital, London SE1 9RT, United Kingdom.
Skowera
Ania
A
Arif
Sefina
S
Peakman
Mark
M
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D029822:Enterovirus B, Human / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C089732:P2-C protein, Coxsackievirus; D014764:Viral Proteins; D005968:Glutamate Decarboxylase