The loss of immunodominant epitopes affects interferon-gamma production and lytic activity of the human influenza virus-specific cytotoxic T lymphocyte response in vitro.
In the present study, we examined the effect of the loss of the human leucocyte antigen (HLA)-B*3501-restricted nucleoprotein (NP)(418-426) epitope on interferon (IFN)-gamma-production and lytic activity of the human cytotoxic T lymphocyte (CTL) response in vitro. Extensive amino acid variation at T cell receptor contact residues of the NP(418-426) epitope has led to repeated evasion from specific CTL. We generated recombinant influenza viruses with variants of the NP(418-426) epitope, which were used to stimulate peripheral blood mononuclear cells obtained from six HLA-B*3501-positive study subjects in order to expand virus-specific CTL. Loss of the NP(418-426) epitope resulted in a significant reduction of IFN-gamma-expressing CD8+ T cells, similar to that observed previously after the loss of the HLA-B*2705-restricted NP(383-391) epitope. In addition, the effect of the loss of the NP(418-426) epitope on the lytic activity of the virus-specific CTL response was assessed. Also this functional property of the virus-specific CTL response was affected significantly by the loss of this and the NP(383-391) epitope, as determined using the newly developed fluorescent antigen-transfected target cell (FATT)-CTL assay. These findings indicate that the loss of single immunodominant epitopes affects the functionality of the virus-specific CTL response significantly.
Berkhoff
E G M
EG
Department of Virology and Postgraduate School of Molecular Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Geelhoed-Mieras
M M
MM
Verschuren
E J
EJ
van Baalen
C A
CA
Gruters
R A
RA
Fouchier
R A M
RA
Osterhaus
A D M E
AD
Rimmelzwaan
G F
GF
D000328:Adult; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D015796:HLA-B27 Antigen; D015797:HLA-B35 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; C500431:HLA-B*35:01 antigen; D015796:HLA-B27 Antigen; D015797:HLA-B35 Antigen; D016056:Immunodominant Epitopes; D007371:Interferon-gamma