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Disregulated Influenza A Virus-Specific CD8⁺ T Cell Homeostasis in the Absence of IFN- Signaling¹

Stephen J. Turner^2,*,, Elvia Olivas^*, Astrid Gutierrez^*, Gabriela Diaz^* and Peter C. Doherty^*,

^* Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

Recent studies indicate that IFN- 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- (IFN-^–/–) or deficient for the IFN- 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-^–/– mice. Comparable effects were observed for WT mice treated with a neutralizing IFN--specific mAb. Transfer of WT memory Thy1.1⁺ CD8⁺ populations into Thy1.2⁺ B6 IFN-^–/– or IFNGR1^–/– mice followed by intranasal virus challenge demonstrated both that IFN- produced by the host was important for the regulation of Ag-specific CTL numbers and that IFN- 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-^–/– vs WT B6 mice. The present analysis is the first comprehensive demonstration that IFN- signaling can differentially regulate both Ag-specific CTL homeostasis in secondary lymphoid organs and trafficking to a site of virus-induced pathology.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a National Health and Medical Research Council of Australia Burnet Award (to P.C.D.) and a R. D. Wright Fellowship (to S.J.T.), by Science, Technology, and Innovation funds from the Government of Victoria, Australia, by Grant AI29579 from the U.S. Public Health Service, National Institutes of Health, and by ALSAC, St. Jude Children’s Research Hospital.

² Address correspondence and reprint requests to Dr. Stephen J. Turner, Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia. E-mail address: sjturn{at}unimelb.edu.au

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; PA, polymerase A; BAL, bronchoalveolar lavage; MLN, mediastinal lymph node; i.n., intranasally; EID₅₀, egg ID₅₀; NP, nucleoprotein; WT, wild type.

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