Profound Protection against Respiratory Challenge with a Lethal H7N7 Influenza A Virus by Increasing the Magnitude of CD8+T-Cell Memory

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Abstract
The recall of CD8+T-cell memory established by infectingH-2bmice with an H1N1 influenza A virus provided a measure of protection against an extremely virulent H7N7 virus. The numbers of CD8+effector and memory T cells specific for the shared, immunodominant DbNP366epitope were greatly increased subsequent to the H7N7 challenge, and though lung titers remained as high as those in naive controls for 5 days or more, the virus was cleared more rapidly. Expanding the CD8+memory T-cell pool (10%) by sequential priming with two different influenza A viruses (H3N2→H1N1) gave much better protection. Though the H7N7 virus initially grew to equivalent titers in the lungs of naive and double-primed mice, the replicative phase was substantially controlled within 3 days. This tertiary H7N7 challenge caused little increase in the magnitude of the CD8+DbNP366+T-cell pool, and only a portion of the memory population in the lymphoid tissue could be shown to proliferate. The great majority of the CD8+DbNP366+set that localized to the infected respiratory tract had, however, cycled at least once, though recent cell division was shown not to be a prerequisite for T-cell extravasation. The selective induction of CD8+T-cell memory can thus greatly limit the damage caused by a virulent influenza A virus, with the extent of protection being directly related to the number of available responders. Furthermore, a large pool of CD8+memory T cells may be only partially utilized to deal with a potentially lethal influenza infection.