Responses of coxsackievirus B4-specific T-cell lines to 2C protein-characterization of epitopes with special reference to the GAD65 homology region.
Coxsackie B viruses (CBV) have been indicated as environmental triggers initiating autoimmune destruction of insulin-producing pancreatic beta-cells, and molecular mimicry might be the mechanism. A prime candidate for inducing cross-reactive immune responses is a homology sequence, PEVKEK, found both in CBV4 2C protein and in GAD65. To characterize the CBV4-specific T-cell epitopes, overlapping peptides covering the 2C protein were synthesized and CBV4-specific T-cell lines were established from healthy and diabetic subjects. The T-cell epitopes were dependent on the HLA-DR genotype of the T-cell donor, but no difference between diabetic and healthy subjects could be detected. Peptide p4, which included the PEVKEK sequence, contained an HLA-DR1-restricted T-cell epitope. Three randomly selected CBV4-specific T-cell lines, which responded to peptide p4, failed to recognize GAD65 protein or GAD65 peptides containing the PEVKEK sequence. We conclude that the CBV4 2C protein is strongly immunogenic for T-cells and PEVKEK is included in a T-cell epitope. However, presentation of this epitope in the context of neutral HLA-DR1 allele does not support its role in pathogenesis of type 1 diabetes.
Marttila
J
J
JDFI Centre for Diabetes Prevention in Finland, University of Turku, Turku, FIN-20520, Finland. jane.marttila@utu.fi
Juhela
S
S
Vaarala
O
O
Hyöty
H
H
Roivainen
M
M
Hinkkanen
A
A
Vilja
P
P
Simell
O
O
Ilonen
J
J
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology*; D002455:Cell Division; D002460:Cell Line; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000821:virology; D004770:Enterovirus / Q000235:genetics* / Q000276:immunology*; D018604:Epitope Mapping; D005968:Glutamate Decarboxylase / Q000235:genetics*; D015798:HLA-DR1 Antigen / Q000235:genetics; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism / Q000821:virology; D007527:Isoenzymes / Q000235:genetics*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000494:pharmacology*
D002352:Carrier Proteins; D016207:Cytokines; D015798:HLA-DR1 Antigen; D007527:Isoenzymes; D017361:Viral Nonstructural Proteins; C076023:2C protein, viral; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2