Recent studies indicate that IFN-γ may influence both the expansion and the trafficking of virus-specific CD8+ CTL, though the effects are not necessarily consistent for different models of viral and bacterial disease. Influenza A virus infection of mice deficient for IFN-γ (IFN-γ−/−) or deficient for the IFN-γ receptor 1 (IFNGR1−/−) was, when compared with the wild-type (WT) B6 controls, associated with increased Ag-specific CD8+ T cell counts in the spleen and mediastinal lymph nodes. At the same time, fewer of these CTL effectors were found in the bronchoalveolar lavage population recovered from the IFN-γ−/− mice. Comparable effects were observed for WT mice treated with a neutralizing IFN-γ-specific mAb. Transfer of WT memory Thy1.1+ CD8+ populations into Thy1.2+ B6 IFN-γ−/− or IFNGR1−/− mice followed by intranasal virus challenge demonstrated both that IFN-γ produced by the host was important for the regulation of Ag-specific CTL numbers and that IFN-γ was likely to act directly on the T cells themselves. In addition, the prevalence of CTLs undergoing apoptosis in spleen was lower when measured directly ex vivo for IFN-γ−/− vs WT B6 mice. The present analysis is the first comprehensive demonstration that IFN-γ signaling can differentially regulate both Ag-specific CTL homeostasis in secondary lymphoid organs and trafficking to a site of virus-induced pathology.

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The restriction of influenza A virus replication to mouse respiratory epithelium means that this host response is anatomically compartmentalized, on the one hand, to sites of T cell stimulation and proliferation in the secondary lymphoid tissue and, on the other hand, to the site of effector T cell function and pathology in the pneumonic lung. Thus, it is hardly surprising that virus-specific CD8 ؉ T cells recovered by bronchoalveolar lavage (BAL) from the infected respiratory tract seem more ''activated'' in terms of both cytolytic activity and cytokine production than those cells isolated from the spleen. The present analysis uses Affymetrix microarray technology to compare profiles of gene expression in these two lineage-related, yet anatomically separate, lymphocyte populations. Ninety differentially expressed genes were identified for influenza-specific CD8 ؉ D b NP 366 ؉ T cells obtained directly ex vivo by BAL or spleen disruption, with nine genes being further analyzed by quantitative, real-time PCR at the population level. Integrin ␣E, for example, was shown by Affymetrix and real-time mRNA analyses and then by single-cell PCR and protein staining to be present at a much higher prevalence on the BAL CD8 ؉ D b NP366 ؉ set. The unpredicted finding, however, was that mRNA expression for 75% of the 90 genes was lower in T cells from the BAL than from the spleen. Apparently, the localization of virus-specific CD8 ؉ T cells to the site of virus-induced pathology is associated with a narrowing, or ''focusing,'' of gene expression that favors enhanced effector function in the damaged, ''high-antigen load'' environment of the pneumonic lung.Affymetrix gene array ͉ cytotoxic T cell ͉ influenza A virus ͉ viral immunology

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