The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic ␥-herpesvirus. Both CD4 ؉ and CD8 ؉ T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers in the lung. However, the further neutralization of IFN-␥ diminishes the effectiveness of the CD4 ؉ T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4 ؉ effectors operate optimally when there is the potential for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-␥ produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent depletion of both the CD4 ؉ population and IFN-␥. These experiments raise the possibility that the defective control of intercurrent ␥-herpesvirus infections in patients with AIDS not only is due solely to the absence of helper T cells but also ref lects the loss of an important set of CD4؉ effectors.The ␥-herpesviruses (HVs) cause persistent infections with the potential for tumorigenesis (1-4). The most thoroughly analyzed is Epstein-Barr virus (EBV), which establishes first as a lytic infection of epithelial cells in the oropharynx, followed by lifelong latency in B lymphocytes. The acute phase is rapidly controlled by the specific host response, whereas continued immune surveillance by CD8 ϩ

The recall of CD8؉ T-cell memory established by infecting H-2 b mice 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 D b NP 366 epitope 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 (<0.5 to >10%) by sequential priming with two different influenza A viruses (H3N23H1N1) 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 ؉ D b NP 366 ؉ 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 ؉ D b NP 366 ؉ 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.

Optimal expansion of influenza virus nucleoprotein (D b NP 366 )-specific CD8 ؉ T cells following respiratory challenge of naive Ig؊/؊ MT mice was found to require CD4 ؉ T-cell help, and this effect was also observed in primed animals. Absence of the CD4 ؉ population was consistently correlated with diminished recruitment of virus-specific CD8 ؉ T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8؉ set generated during the recall response in Ig ؊/؊ mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4 ؉ T-cell response. Both the magnitude and the localization profiles of virus-specific CD8 ؉ T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4 ؉ T cells.

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