Intracellular Signaling by the Killer Immunoglobulin-Like Receptors and Ly49

Daniel W. McVicar, and Deborah N. Burshtyn

D. W. McVicar is at the Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute, NCI-FCRDC Building 560/Rm 31-93, Frederick, MD 21702, USA. E-mail: McVicar{at}nih.gov
D. N. Burshtyn is at the Department of Medical Microbiology and Immunology, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada.

Natural killer (NK) cells patrol the blood and immune organs in search of infected or malignant cells. Research suggests that these cells query a potential target cell for surface proteins that identify it as a healthy, self-derived cell. If the NK cell fails to recognize self markers because they have been down-regulated due to malignant transformation or viral infection, the NK cell kills the target. Scientists now have a clearer understanding of how NK cells discriminate between healthy and diseased cells. NK surface proteins called killer cell immunoglobulin-like receptors (KIRs) in humans, and Ly49 receptors in the mouse, recognize the markers of self. Once engaged, specific intracellular regions of the receptors are modified to recruit enzymes capable of reversing the biochemical events within the NK cell that would otherwise lead it to kill the target. Surprisingly, some KIRs and Ly49 receptors recognize the same self markers but send activation signals to NK cells. It is unclear why these cells would want a system of receptors that both activate and inhibit, thus potentially canceling one another out, but the method of this madness is clear. Activating KIRs or Ly49s lack inhibitory characteristics and instead interact with a second protein called DAP12, which contains an immunoreceptor tyrosine-based activation motif that functions to recruit activating enzymes. The result is a biochemical system of Yin and Yang where some receptors shut down responses and others activate them. Through tight regulation of the expression of these receptors, the NK cell is careful to seek out and kill only those cells identified as infected, damaged, or malignant.

Citation:
D. W. McVicar, D. N. Burshtyn, Intracellular Signaling by the Killer Immunoglobulin-Like Receptors and Ly49. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/75/re1.

© 2001 American Association for the Advancement of Science