Author:
Gamache Awndre,Cronk John M.,Nash William T.,Puchalski Patryk,Gillespie Alyssa,Wei Hairong,Gray Laurie,Hammarskjold Marie-Louise,Xu Wenhao,Brown Michael G.
Abstract
Natural killer (NK) cells mediate vital control of cancer and viral infection. They rely on MHC class I (MHC I)-specific self-receptors to identify and lyse diseased cells without harming self-MHC I-bearing host cells. NK cells bearing inhibitory self-receptors for host MHC I also undergo education, referred to as licensing, which causes them to become more responsive to stimulation via activation receptor signaling. Previous work has shown that licensed NK cells selectively expand during virus infections and they are associated with improved clinical response in human patients experiencing certain chronic virus infections, including HIV and hepatitis C virus. However, the importance of inhibitory self-receptors in NK-mediated virus immunity is debated as they also limit signals in NK cells emanating from virus-specific activation receptors. Using a mouse model of MHC I-dependent (H-2Dk) virus immunity, we discovered that NK cells depend on the Ly49G2 inhibitory self-receptor to mediate virus control, which coincided with host survival during murine cytomegalovirus infection. This antiviral effect further requires active signaling in NK cells via the Ly49R activation receptor that also binds H-2Dk. In tandem, these functionally discordant Ly49 self-receptors increase NK cell proliferation and effector activity during infection, resulting in selective up-regulation of CD25 and KLRG1 in virus-specific Ly49R+Ly49G2+NK cells. Our findings establish that paired self-receptors act as major determinants of NK cell-mediated virus sensing and immunity.
Funder
HHS | NIH | National Institute of Allergy and Infectious Diseases
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Publisher
Proceedings of the National Academy of Sciences
Cited by
8 articles.
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