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Journal of Virology, February 2003, p. 2469-2476, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2469-2476.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Lack of Tumor Necrosis Factor Alpha Induces Impaired Proliferation of Hepatitis B Virus-Specific Cytotoxic T Lymphocytes

Senji Kasahara,1 Kazuki Ando,1* Kuniaki Saito,2 Kenji Sekikawa,3 Hiroyasu Ito,1 Tetsuya Ishikawa,4 Hiroo Ohnishi,5 Mitsuru Seishima,2 Shinichi Kakumu,4 and Hisataka Moriwaki1

First Department of Internal Medicine,1 Department of Laboratory Medicine, Gifu University School of Medicine,2 Department of Gastroenterology, Gifu Prefectural Gifu Hospital, Gifu,5 Department of Immunology, National Institute of Animal Health, Tsukuba,3 Division of Gastroenterology, Department of Internal Medicine, Research Center for Infectious Disease, Aichi Medical University School of Medicine, Aichi, Japan4

Received 6 August 2002/ Accepted 7 November 2002

Recent studies have shown that tumor necrosis factor alpha (TNF-{alpha}) plays critical roles in not only viral clearance but also lymphoid tissue development and stem cell differentiation. In this study, we attempted to induce hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) by immunization of TNF-{alpha} knockout (TNF-{alpha}-/-) mice with HBsAg-encoding plasmid DNA. An immunization with the HBV plasmid failed to induce CTL responses in TNF-{alpha}-/- mice, although CTLs were readily induced in wild-type mice by the same protocol. Weak CTL responses were produced in TNF-{alpha}-/- mice after two sessions of immunization with the HBV plasmid; however, TNF-{alpha} was required to maintain the responses of these CTL lines to in vitro stimulation and, even then, the responses were lost after 3 weeks. Interestingly, a limiting dilution of a CTL line showed that HBV-specific CTL clones with high specific cytotoxicity were present in TNF-{alpha}-/- mice, but these clones again failed to proliferate for more than 3 weeks. Furthermore, since exogenously added TNF-{alpha} enhanced the proliferation of a TNF-{alpha}-/- clone but suppressed that of a TNF-{alpha}+/+ clone in vitro, TNF-{alpha} also has a direct effect on the proliferation of CTLs. In conclusion, TNF-{alpha} is essential rather than important for the proliferation of HBV-specific CTLs both in vivo and in vitro and this effect is not only due to the activation of dendritic cells but is also induced by the direct effect on CTLs.

* Corresponding author. Mailing address: First Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. Phone: 81-58-267-2843. Fax: 81-58-262-8484. E-mail: kazu62{at}cc.gifu-u.ac.jp.

Journal of Virology, February 2003, p. 2469-2476, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2469-2476.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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