Journal
NATURE IMMUNOLOGY
Volume 19, Issue 10, Pages 1083-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0209-9
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Funding
- EFIS-IL Short-term Fellowship
- European Research Council under the European Union's Seventh Framework Programme (FP)/ERC [311335]
- Swedish Research Council
- Norwegian Research Council
- Swedish Foundation for Strategic Research
- Wallenberg Foundation
- Swedish Cancer Foundation
- Swedish Childhood Cancer Foundation
- Stockholm County Council
- Karolinska Institutet Center for Innovative Medicine
- Netherlands Organization for Scientific Research [91614029]
- European Commission [PCIG14-GA-2013-630827]
- University of Rijeka [865.10.2101, 803.10.1103]
- European Social Fund [HR.3.2.01-0263]
- Croatian Science Foundation [IP-2016-06-9306, KK.01.1.1.01.0006, IP-2016-06-8027]
- European Regional Development Fund
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The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1(-/-)) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-gamma. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3 zeta. Reduced expression of CD3. in Klrk1(-/-) mice was associated with enhanced signal transduction through NCR1, and CD3. deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.
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