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International Immunology Advance Access published online on December 16, 2005
International Immunology, doi:10.1093/intimm/dxh337
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received April 19, 2005
Accepted September 16, 2005

Article

Activation of V{gamma}9V{delta}2 T cells by non-peptidic antigens induces the inhibition of subgenomic HCV replication

Chiara Agrati 1 *, Tonino Alonzi 1 *, Rafaella De Santis 1, Concetta Castilletti 1, Isabella Abbate 1, Maria Rosaria Capobianchi 1, Gianpiero D'Offizi 1, Francesca Siepi 1, Gian Maria Fimia 1, Marco Tripodi 2, and Fabrizio Poccia 1 *

1 Laboratory of Cellular Immunology, Laboratory of Gene Expression, Laboratory of Virology, Clinical Department, National Institute for Infectious Diseases "Lazzaro Spallanzani"--IRCCS, Via Portuense 292, 00149 Rome, Italy
2 Laboratory of Cellular Immunology, Laboratory of Gene Expression, Laboratory of Virology, Clinical Department, National Institute for Infectious Diseases "Lazzaro Spallanzani"--IRCCS, Via Portuense 292, 00149 Rome, Italy; Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome ‘La Sapienza’, 00161 Rome, Italy

* To whom correspondence should be addressed.
Fabrizio Poccia, E-mail: poccia{at}inmi.it


  Abstract

Hepatitis C virus (HCV) has evolved complex strategies to evade host immune responses and establish chronic infection. Since human V{gamma}9V{delta}2 T lymphocytes play a critical role in the immune response against viruses, we analyzed their antiviral functions on Huh7 hepatoma cells carrying the subgenomic HCV replicon (Rep60 cells). In a transwell culture system, Rep60 cells were co-cultured with either PBMCs or highly purified {gamma}{delta} T cells stimulated by non-peptidic antigens. V{gamma}9V{delta}2 T cell activation was associated with a dramatic reduction of HCV RNA levels. Neutralizing antibodies targeting IFN-{gamma} revealed a critical role for this cytokine in the inhibition of HCV replication. Interestingly, drugs already in clinical use, such as Phosphostim and Zoledronate, known to activate {gamma}{delta} T cells, were shown to induce the inhibition of HCV replication mediated by V{gamma}9V{delta}2 T cells of HCV patients. Our data suggest that the therapeutic activation of V{gamma}9V{delta}2 T lymphocytes may represent an additional strategy to inhibit HCV replication and to restore a Th1-oriented immune response in HCV-infected patients.

Keywords: hepatitis C; IFN-{gamma}; natural immunity; {gamma}{delta} T cells.

*These authors contributed equally to this work.


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