1. Significant Impact of Sequence Variations in the Nucleoprotein on CD8 T Cell-Mediated Cross-Protection against Influenza A Virus Infections
- Author
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Weimin Zhong, Xiuhua Lu, Jacqueline M. Katz, Ellis L. Reinherz, Kathy Hancock, Libo Dong, Suryaprakash Sambhara, and Feng Liu
- Subjects
Cellular immunity ,Cross Protection ,lcsh:Medicine ,Priming (immunology) ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Antibodies, Viral ,Epitope ,Epitopes ,Mice ,0302 clinical medicine ,Influenza A virus ,Cytotoxic T cell ,lcsh:Science ,Genetics ,0303 health sciences ,Multidisciplinary ,3. Good health ,Female ,Research Article ,Immunology ,Molecular Sequence Data ,Receptors, Antigen, T-Cell ,Biology ,Virus ,03 medical and health sciences ,Viral Proteins ,Cross-Priming ,Antigen ,Orthomyxoviridae Infections ,Immunology/Immunity to Infections ,Influenza, Human ,medicine ,Animals ,Humans ,Amino Acid Sequence ,030304 developmental biology ,Mucous Membrane ,lcsh:R ,Immunity ,Genetic Variation ,Virology ,Lymphocyte Subsets ,Nucleoprotein ,Nucleoproteins ,Immunology/Immune Response ,lcsh:Q ,Immunologic Memory ,030215 immunology ,T-Lymphocytes, Cytotoxic - Abstract
Background: Memory CD8 T cells to influenza A viruses are widely detectable in healthy human subjects and broadly crossreactive for serologically distinct influenza A virus subtypes. However, it is not clear to what extent such pre-existing cellular immunity can provide cross-subtype protection against novel emerging influenza A viruses. Methodology/Principal Findings: We show in the mouse model that naturally occurring sequence variations of the conserved nucleoprotein of the virus significantly impact cross-protection against lethal disease in vivo. When priming and challenge viruses shared identical sequences of the immunodominant, protective NP366/D b epitope, strong cross-subtype protection was observed. However, when they did not share complete sequence identity in this epitope, cross-protection was considerably reduced. Contributions of virus-specific antibodies appeared to be minimal under these circumstances. Detailed analysis revealed that the magnitude of the memory CD8 T cell response triggered by the NP366/D b variants was significantly lower than those triggered by the homologous NP366/D b ligand. It appears that strict specificity of a dominant public TCR to the original NP366/D b ligand may limit the expansion of cross-reactive memory CD8 T cells to the NP366/D b variants. Conclusions/Significance: Pre-existing CD8 T cell immunity may provide substantial cross-protection against heterosubtypic influenza A viruses, provided that the priming and the subsequent challenge viruses share the identical sequences of the immunodominant, protective CTL epitopes.
- Published
- 2010