The Journal of Experimental Medicine
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Published 25 March 2002. doi:10.1084/jem.20011427
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© Rockefeller University Press, 0022-1007/2002/4/825/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 7, April 1, 2002 825-834

Original Article

Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection

Hanna Sjölin1, Elena Tomasello2, Mehrdad Mousavi-Jazi3, Armando Bartolazzi4, Klas Kärre1, Eric Vivier2 and Cristina Cerboni1

1 Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
2 Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille cedex 09, France
3 Department of Virology, Swedish Institute for Infectious Disease Control, S 171 77 Stockholm, Sweden
4 Department of Pathology, Cancer Center Karolinska, Karolinska Hospital, S 171 76 Stockholm, Sweden

Address correspondence to Cristina Cerboni, Microbiology and Tumor Biology Center, Karolinska Institute, Nobels väg 16, BOX 280, S 171 77 Stockholm, Sweden. Phone: 46-8-7286768; Fax: 46-8-304276; E-mail: cristina.cerboni{at}mtc.ki.se

Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30–40-fold) and in the liver (2–5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon {gamma} was reduced by 56 ± 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell–mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H.

Key Words: animal models • activating receptors • signal transduction • pathogens • cytokines


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