Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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

Copyright © 2011 by the Rockefeller University Press.


Article

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}mskcc.org

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



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse.
A. Le Floc'h, Y. Tanaka, N. S. Bantilan, G. Voisinne, G. Altan-Bonnet, Y. Fukui, and M. Huse (2013)
J. Exp. Med. 210, 2721-2737
   Abstract »    Full Text »    PDF »
Superresolution Microscopy Reveals Nanometer-Scale Reorganization of Inhibitory Natural Killer Cell Receptors upon Activation of NKG2D.
S. V. Pageon, S.-P. Cordoba, D. M. Owen, S. M. Rothery, A. Oszmiana, and D. M. Davis (2013)
Science Signaling 6, ra62
   Abstract »    Full Text »    PDF »
NK Cell Tolerance of Self-Specific Activating Receptor KIR2DS1 in Individuals with Cognate HLA-C2 Ligand.
G. Pittari, X.-R. Liu, A. Selvakumar, Z. Zhao, E. Merino, M. Huse, J. H. Chewning, K. C. Hsu, and B. Dupont (2013)
J. Immunol. 190, 4650-4660
   Abstract »    Full Text »    PDF »
Protein Kinase C-{theta} Clustering at Immunological Synapses Amplifies Effector Responses in NK Cells.
E. Merino, T. P. Abeyweera, M. A. Firth, C. L. Zawislak, R. Basu, X. Liu, J. C. Sun, and M. Huse (2012)
J. Immunol. 189, 4859-4869
   Abstract »    Full Text »    PDF »
Cell-Mediated Autophagy Promotes Cancer Cell Survival.
W. J. Buchser, T. C. Laskow, P. J. Pavlik, H.-M. Lin, and M. T. Lotze (2012)
Cancer Res. 72, 2970-2979
   Abstract »    Full Text »    PDF »
Natural Killer Cell Tolerance: Control by Self or Self-Control?.
B. N. Jaeger and E. Vivier (2012)
Cold Spring Harb Perspect Biol 4, a007229
   Abstract »    Full Text »    PDF »
Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally.
A. Kaplan, S. Kotzer, C. R. Almeida, R. Kohen, G. Halpert, M. Salmon-Divon, K. Kohler, P. Hoglund, D. M. Davis, and R. Mehr (2011)
J. Immunol. 187, 760-773
   Abstract »    Full Text »    PDF »
Inhibitory signaling blocks activating receptor clustering and induces cytoskeletal retraction in natural killer cells.
T. P. Abeyweera, E. Merino, and M. Huse (2011)
J. Exp. Med. 208, i4
Natural killer cells commute death sentence.
M. Leslie (2011)
J. Cell Biol. 192, 542
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882