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Published online on October 2, 2001, 10.1073/pnas.211423598
PNAS | October 9, 2001 | vol. 98 | no. 21 | 12162-12167


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Immunology
 TNF-alpha -dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection

Jose M. Trevejo*,dagger , Michael W. MarinoDagger , Nicola Philpott*, Regis Josien§, Elizabeth C. RichardsDagger , Keith B. Elkon, and Erik Falck-Pedersen*,||

* Department of Microbiology and Immunology, WJ Hearst Foundation, Weill Medical College of Cornell University, New York, NY 10021; dagger  The Cornell-Rockefeller-Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY 10021; Dagger  Ludwig Institute for Cancer Research, Memorial-Sloan Kettering Cancer Center, New York, NY 10021; § Service de Nephrologie-Immunologie Clinique, Centre Hospitalier Régional Universitaire de Nantes, Immeuble Jean Monnet, 44093 Nantes Cedex 01, France; and  Hospital for Special Surgery, New York, NY 10021

Communicated by Lloyd J. Old, Ludwig Institute for Cancer Research, New York, August, 10, 2001 (received for review March 5, 2001)

Tumor necrosis factor-alpha (TNF-alpha ) is well recognized for its role in mediating innate immune responses. However, the mechanisms of TNF-alpha that influence the adaptive immune response to virus infections are not well understood. In this study, we have investigated the role of TNF-alpha in activating the cellular and humoral responses to systemic viral challenge with recombinant replication-defective adenovirus (rAd). Evaluation of T cell function in TNF-alpha -deficient (TNFKO) mice revealed impaired virus-specific proliferation of T cells derived from the draining lymph nodes of the liver. Analysis of dendritic cells (DC) isolated from local draining lymph nodes after systemic challenge showed that DC from TNFKO mice were relatively immature compared with those from strain-matched wild-type mice. In vitro, TNF-alpha was required to mature DC efficiently during virus-mediated stimulation. Adoptive transfer of primed, mature DC into TNFKO mice restored T cell responses and reconstituted anti-adenovirus antibody responses. Thus, TNF-alpha plays a significant role in the maturation of DC after adenovirus challenge both in vitro and in vivo, highlighting the importance of this innate cytokine in activating adaptive immunity to viral challenge.

|| To whom reprint requests should be addressed. E-mail: efalckp{at}med.cornell.edu.

www.pnas.org/cgi/doi/10.1073/pnas.211423598
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