The Journal of Experimental Medicine
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Published online 23 December 2002 doi:10.1084/jem.20020427
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© Rockefeller University Press, 0022-1007/2003/1/77 $5.00
The Journal of Experimental Medicine, Volume 197, Number 1, 77-85

Natural Killer Cell Inhibitory Receptors Block Actin Cytoskeleton-dependent Recruitment of 2B4 (CD244) to Lipid Rafts

Carsten Watzl1,2 and Eric O. Long1

1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
2 Institute for Immunology, University Heidelberg, INF 305, 69120 Heidelberg, Germany

Address correspondence to E.O. Long, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Dr., Rockville, MD 20852. Phone: 301-496-8266; Fax: 301-402-0259; E-mail: elong{at}nih.gov

A dynamic balance of positive and negative signals regulates target cell lysis by natural killer (NK) cells upon engagement of a variety of different activation receptors and of inhibitory receptors that recruit the tyrosine phosphatase SHP-1. However, the step at which activation signals are blocked by SHP-1 is not known. We have been using activation receptor 2B4 (CD244) to study the influence of inhibitory receptors on NK cell activation. Engagement of inhibitory receptors by HLA class I on target cells blocks phosphorylation of 2B4, placing the inhibitory step at the level, or upstream of 2B4 phosphorylation. Here we show that phosphorylated 2B4, after engagement with either antibodies or target cells that express the 2B4 ligand, is found exclusively in a detergent-resistant membrane fraction that contains lipid rafts. Integrity of lipid rafts was essential for phosphorylation and activating function of 2B4. Coengagement of inhibitory receptors blocked 2B4 phosphorylation and 2B4 association with detergent-resistant membranes, indicating that inhibitory receptors function upstream of raft-dependent signals. Recruitment of 2B4 into detergent-resistant membrane fractions and 2B4 phosphorylation were dependent on actin polymerization. Blocking actin cytoskeleton-dependent raft recruitment of different receptors may be a general mechanism by which inhibitory receptors control NK cell activation.

Key Words: natural killer cell • raft • tyrosine phosphorylation • inhibitory receptor • activation


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