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 γ 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.
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1 April 2002
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March 25 2002
Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection
Hanna Sjölin,
Hanna Sjölin
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
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Elena Tomasello,
Elena Tomasello
2Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille cedex 09, France
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Mehrdad Mousavi-Jazi,
Mehrdad Mousavi-Jazi
3Department of Virology, Swedish Institute for Infectious Disease Control, S 171 77 Stockholm, Sweden
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Armando Bartolazzi,
Armando Bartolazzi
4Department of Pathology, Cancer Center Karolinska, Karolinska Hospital, S 171 76 Stockholm, Sweden
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Klas Kärre,
Klas Kärre
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
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Eric Vivier,
Eric Vivier
2Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille cedex 09, France
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Cristina Cerboni
Cristina Cerboni
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
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Hanna Sjölin
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
Elena Tomasello
2Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille cedex 09, France
Mehrdad Mousavi-Jazi
3Department of Virology, Swedish Institute for Infectious Disease Control, S 171 77 Stockholm, Sweden
Armando Bartolazzi
4Department of Pathology, Cancer Center Karolinska, Karolinska Hospital, S 171 76 Stockholm, Sweden
Klas Kärre
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 Stockholm, Sweden
Eric Vivier
2Centre d'Immunologie INSERM/CNRS de Marseille-Luminy, Case 906, 13288 Marseille cedex 09, France
Cristina Cerboni
1Microbiology and Tumor Biology Center, Karolinska Institute, S 171 77 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: [email protected]
*
Abbreviations used in this paper: ITAM, immunoreceptor tyrosine-based activatory motif; MCMV, murine CMV; MFI, median of fluorescence intensity; MIP-1α, macrophage inflammatory protein-1α.
Received:
August 16 2001
Revision Received:
February 05 2002
Accepted:
February 20 2002
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2002
J Exp Med (2002) 195 (7): 825–834.
Article history
Received:
August 16 2001
Revision Received:
February 05 2002
Accepted:
February 20 2002
Citation
Hanna Sjölin, Elena Tomasello, Mehrdad Mousavi-Jazi, Armando Bartolazzi, Klas Kärre, Eric Vivier, Cristina Cerboni; Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection . J Exp Med 1 April 2002; 195 (7): 825–834. doi: https://doi.org/10.1084/jem.20011427
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