The Journal of Experimental Medicine
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Published 31 December 2001. doi:10.1084/jem.20011124
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© Rockefeller University Press, 0022-1007/2002/1/35/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 1, January 7, 2002 35-42

Original Article

Inhibition of Natural Killer Cells through Engagement of CD81 by the Major Hepatitis C Virus Envelope Protein

Stefania Crotta1, Annalisa Stilla1, Andreas Wack1, Annalisa D'Andrea1, Sandra Nuti1, Ugo D'Oro1, Marta Mosca2, Franco Filliponi2, R. Maurizia Brunetto2, Ferruccio Bonino2, Sergio Abrignani1 and Nicholas M. Valiante1

1 IRIS, Department of Immunology, Chiron S.p.A., 53100 Siena, Italy
2 Department of Gastroenterology and Hepatology, Ospedale Cisanello, 56124 Pisa, Italy

Address correspondence to N.M. Valiante, Dept. of Immunology, IRIS, Chiron, S.p.A. Via Fiorentina 1, 53100 Siena, Italy. Phone: 39-0577-243491; Fax: 39-0577-243564; E-mail: Nicholas_Valiante{at}Chiron.com

The immune response against hepatitis C virus (HCV) is rarely effective at clearing the virus, resulting in ~170 million chronic HCV infections worldwide. Here we report that ligation of an HCV receptor (CD81) inhibits natural killer (NK) cells. Cross-linking of CD81 by the major envelope protein of HCV (HCV-E2) or anti-CD81 antibodies blocks NK cell activation, cytokine production, cytotoxic granule release, and proliferation. This inhibitory effect was observed using both activated and resting NK cells. Conversely, on NK-like T cell clones, including those expressing NK cell inhibitory receptors, CD81 ligation delivered a costimulatory signal. Engagement of CD81 on NK cells blocks tyrosine phosphorylation through a mechanism which is distinct from the negative signaling pathways associated with NK cell inhibitory receptors for major histocompatibility complex class I. These results implicate HCV-E2–mediated inhibition of NK cells as an efficient HCV evasion strategy targeting the early antiviral activities of NK cells and allowing the virus to establish itself as a chronic infection.

Key Words: natural killer cells • inhibitory signaling • immune evasion • chronic viral infection • tetraspanin


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