T-cell tolerance for variability in an HLA class I-presented influenza A virus epitope.
To escape immune recognition, viruses acquire amino acid substitutions in class I human leukocyte antigen (HLA)-presented cytotoxic T-lymphocyte (CTL) epitopes. Such viral escape mutations may (i) prevent peptide processing, (ii) diminish class I HLA binding, or (iii) alter T-cell recognition. Because residues 418 to 426 of the hypervariable influenza A virus nucleoprotein (NP(418-426)) epitope are consistently bound by class I HLA and presented to CTL, we assessed the impact that intraepitope sequence variability has upon T-cell recognition. CTL elicited by intranasal influenza virus infection were tested for their cross-recognition of 20 natural NP(418-426) epitope variants. Six of the variant epitopes, of both H1N1 and H3N2 origin, were cross-recognized by CTL while the remaining NP(418-426) epitope variants escaped targeting. A pattern emerged whereby variability at position 5 (P5) within the epitope reduced T-cell recognition, changes at P4 or P6 enabled CTL escape, and a mutation at P8 enhanced T-cell recognition. These data demonstrate that substitutions at P4 and/or P6 facilitate influenza virus escape from T-cell recognition and provide a model for the number, nature, and location of viral mutations that influence T-cell cross-recognition.
Wahl
Angela
A
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.
McCoy
William
WH
Schafer
Fredda
F
Bardet
Wilfried
W
Buchli
Rico
R
Fremont
Daved H
DH
Hildebrand
William H
WH
D017951:Antigen Presentation; D000956:Antigens, Viral; D045142:Cross-Priming; D000939:Epitopes / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D009980:Influenza A virus / Q000276:immunology*; D020125:Mutation, Missense; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology*
D000956:Antigens, Viral; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins