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Inhibitory Receptor Signals Suppress Ligation-Induced Recruitment of NKG2D to GM1-Rich Membrane Domains at the Human NK Cell Immune Synapse¹

Johanna Endt^2,*, Fiona E. McCann^2,, Catarina R. Almeida^2,, Doris Urlaub^*, Rufina Leung, Daniela Pende, Daniel M. Davis^3, and Carsten Watzl^3,*

^* Institute for Immunology, University Heidelberg, Heidelberg, Germany; Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom; and Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

NKG2D is an activating receptor expressed on all human NK cells and a subset of T cells. In cytolytic conjugates between NK cells and target cells expressing its ligand MHC class I chain-related gene A, NKG2D accumulates at the immunological synapse with GM1-rich microdomains. Furthermore, NKG2D is specifically recruited to detergent-resistant membrane fractions upon ligation. However, in the presence of a strong inhibitory stimulus, NKG2D-mediated cytotoxicity can be intercepted, and recruitment of NKG2D to the immunological synapse and detergent-resistant membrane fractions is blocked. Also, downstream phosphorylation of Vav-1 triggered by NKG2D ligation is circumvented by coengaging inhibitory receptors. Thus, we propose that one way in which inhibitory signaling can control NKG2D-mediated activation is by blocking its recruitment to GM1-rich membrane domains. The accumulation of activating NK cell receptors in GM1-rich microdomains may provide the necessary platform from which stimulatory signals can proceed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Fundação para a Ciência e a Tecnologia (to C.R.A.), the Medical Research Council (U.K.), the Biotechnology and Biological Sciences Research Council, and a Lister Institute Research Prize (to D.M.D.), the Deutsche Forschungsgemeinschaft (SFB 405, A13), the Deutsche Krebshilfe, and the BioFuture program by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (to C.W.).

² J.E., F.E.M., and C.R.A. contributed equally.

³ Address correspondence to Dr. Carsten Watzl, Institute for Immunology, University Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany and Dr. Daniel M. Davis, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London, U.K. E-mail addresses: Carsten.watzl{at}urz.uni-heidelberg.de and d.davis{at}imperial.ac.uk

⁴ Abbreviations used in this paper: IS, immunological synapse; MICA, MHC class I chain-related gene A; DRM, detergent-resistant membrane; YFP, yellow fluorescent protein; CFP, cyan fluorescent protein; CTx, cholera toxin subunit B; KIR, killer Ig-like receptor.

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