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¹ Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143
² Department of Immunochemistry, World Premier International Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
³ Department of Discovery Research, Schering-Plough Biopharma, Palo Alto, CA 94304
⁴ Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Aoba, Sendai 980-8575, Japan

CORRESPONDENCE Lewis L. Lanier: Lewis.Lanier{at}ucsf.edu

The activating natural killer (NK) cell receptor Ly49H recognizes the mouse cytomegalovirus (MCMV) m157 glycoprotein expressed on the surface of infected cells and is required for protection against MCMV. Although Ly49H has previously been shown to signal via DAP12, we now show that Ly49H must also associate with and signal via DAP10 for optimal function. In the absence of DAP12, DAP10 enables Ly49H-mediated killing of m157-bearing target cells, proliferation in response to MCMV infection, and partial protection against MCMV. DAP10-deficient Ly49H⁺ NK cells, expressing only Ly49H–DAP12 receptor complexes, are partially impaired in their ability to proliferate during MCMV infection, display diminished ERK1/2 activation, produce less IFN- upon Ly49H engagement, and demonstrate reduced control of MCMV infection. Deletion of both DAP10 and DAP12 completely abrogates Ly49H surface expression and control of MCMV infection. Thus, optimal NK cell–mediated immunity to MCMV depends on Ly49H signaling through both DAP10 and DAP12.

© 2009 Orr et al.
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