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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.    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 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/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.

Significant Impact of Sequence Variations in the Nucleoprotein on CD8 T Cell-Mediated Cross-Protection against Influenza A Virus Infections