Significant impact of sequence variations in the nucleoprotein on CD8 T cell-mediated cross-protection against influenza A virus infections.
BACKGROUND
Memory CD8 T cells to influenza A viruses are widely detectable in healthy human subjects and broadly cross-reactive 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.


RESULTS
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 NP(366)/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 NP(366)/D(b) variants was significantly lower than those triggered by the homologous NP(366)/D(b) ligand. It appears that strict specificity of a dominant public TCR to the original NP(366)/D(b) ligand may limit the expansion of cross-reactive memory CD8 T cells to the NP(366)/D(b) variants.


CONCLUSIONS
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.
Zhong
Weimin
W
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. wzhong@cdc.gov
Liu
Feng
F
Dong
Libo
L
Lu
Xiuhua
X
Hancock
Kathy
K
Reinherz
Ellis L
EL
Katz
Jacqueline M
JM
Sambhara
Suryaprakash
S
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D056738:Cross Protection / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007109:Immunity / Q000276:immunology; D007156:Immunologic Memory; D009980:Influenza A virus / Q000145:classification / Q000276:immunology*; D007251:Influenza, Human / Q000097:blood / Q000276:immunology / Q000821:virology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000276:immunology; D009698:Nucleoproteins / Q000737:chemistry / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000097:blood / Q000276:immunology / Q000821:virology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
D000914:Antibodies, Viral; D000939:Epitopes; D009698:Nucleoproteins; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins