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J. Cell Biol. 192 (4): 675-690

Copyright © 2011 by the Rockefeller University Press.


Inhibitory signaling blocks activating receptor clustering and induces cytoskeletal retraction in natural killer cells

Thushara P. Abeyweera, Ernesto Merino, , and Morgan Huse

Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065

Correspondence to M. Huse: husem{at}

Abstract: Natural killer (NK) lymphocytes use a variety of activating receptors to recognize and kill infected or tumorigenic cells during an innate immune response. To prevent targeting healthy tissue, NK cells also express numerous inhibitory receptors that signal through immunotyrosine-based inhibitory motifs (ITIMs). Precisely how signals from competing activating and inhibitory receptors are integrated and resolved is not understood. To investigate how ITIM receptor signaling impinges on activating pathways, we developed a photochemical approach for stimulating the inhibitory receptor KIR2DL2 during ongoing NK cell–activating responses in high-resolution imaging experiments. Photostimulation of KIR2DL2 induces the rapid formation of inhibitory receptor microclusters in the plasma membrane and the simultaneous suppression of microclusters containing activating receptors. This is followed by the collapse of the peripheral actin cytoskeleton and retraction of the NK cell from the source of inhibitory stimulation. These results suggest a cell biological basis for ITIM receptor signaling and establish an experimental framework for analyzing it.

Abbreviations: DMNB, dimethoxy-nitrobenzyl • Fmoc, 9-fluorenylmethoxycarbonyl • HLA, human leukocyte antigen • ICAM, intercellular adhesion molecule • ITIM, immunotyrosine-based inhibitory motif • KIR, killer Ig receptor • MHC, major histocompatibility complex • MSCV, murine stem cell virus • NK, natural killer • SA, streptavidin • TIRF, total internal reflection fluorescence

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