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* Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642; and
Department of Surgery, University of Wuerzburg, Wuerzburg, Germany
Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell death. To test whether this was the case in an extrahepatic infection, we investigated the fate and effector capacity of intrahepatic CD8+ T cells during lung-restricted influenza infection in mice. Virus-specific T cells accumulated in livers without detectable intrahepatic presentation of viral Ags, and this accumulation was not restricted to the contraction phase, but was apparent as early as day 5. Intrahepatic influenza-specific cells were functionally similar to those recovered from the bronchioalveolar lavage, based on ex vivo cytokine production and specific target lysis. Both adoptive transfer of liver lymphocytes and orthotopic liver transplant of organs containing accumulated effector T cells revealed that activated CD8s from the liver were viable, expanded during reinfection, and generated a memory population that trafficked to lymphoid organs. Thus, intrahepatic CD8+ T cells re-enter circulation and generate functional memory, indicating that the liver does not uniformly incapacitate activated CD8+ T cells. Instead, it constitutes a substantial reservoir of usable Ag-specific effector CD8+ T cells involved in both acute and recall immune responses.
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 grants from the National Institutes of Health (AG021970, AI037554, and ES001247) and Deutsche Forschungsgemeinschaft (KL1403/2-1). N.K.P. was supported by National Institutes of Health/National Research Service Award Training Grant T32 AI-07285.
2 Address correspondence and reprint requests to Dr. David J. Topham, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, 601 Elmwood Avenue, Box 609, Rochester, NY 14642-8609. E-mail address: david_topham{at}urmc.rochester.edu
3 Abbreviations used in this paper: LN, lymph node; BAL, bronchioalveolar lavage; 
-gal, -galactosidase; MLN, mediastinal LN; EID50, 50% egg infectious dose; NLT, nonlymphoid tissue; NP, nucleoprotein; PA, acid polymerase; PR8, influenza A/PR/8/34; x31, influenza A/HK/x31; WSN-OVAI, influenza A/WSN/OVAI.
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