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Cis association of Ly49A with MHC class I restricts natural killer cell inhibition

Nature Immunology volume 5, pages 328–336 (2004)Cite this article

Abstract

Natural killer (NK) cell function is negatively regulated by inhibitory receptors interacting with major histocompatibility complex class I molecules expressed on target cells. Here we show that the inhibitory Ly49A NK cell receptor not only binds to its H-2Dd ligand expressed on potential target cells (in trans) but also is constitutively associated with H-2Dd in cis (on the same cell). Cis association and trans interaction occur through the same binding site. Consequently, cis association restricts the number of Ly49A receptors available for binding of H-2Dd on target cells and reduces NK cell inhibition through Ly49A. By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction allows optimal discrimination of normal and abnormal host cells.

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Figure 1: Ly49A function on H-2Dd-expressing NK cells.
Figure 2: Ly49A function in NK cells from H-2Dd mosaic mice.
Figure 3: MHC class I dependence of Ly49A staining with H-2Dk multimers.
Figure 4: MHC-dependence of H-2Dk multimer staining to Ly49A transfectants.
Figure 5: Ly49A and H-2Dd are associated in the plane of the NK cell membrane.
Figure 6: Ly49A and H-2Dd are physically associated in cis.
Figure 7: Ly49A–H-2Dd interaction in cis and in trans uses an identical binding site.
Figure 8: Induced-self reactivity of Ly49A NK cells.
Figure 9: Model for cis and trans interaction of Ly49A.

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Acknowledgements

We thank Frédéric Levy, Ed Palmer, Olivier Michielin, Jérôme Coudert and Jean-Charles Cerottini for discussions. Supported in part by the Swiss National Science Foundation (W.H. and C.B.), the Swiss Cancer League (W.H.) and the Giorgi-Cavalieri-Foundation (C.B.).

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  1. Marie-Agnès Doucey, Léonardo Scarpellino and Jacques Zimmer: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, Epalinges, 1066, Switzerland

    Marie-Agnès Doucey & Claude Bron

  2. Ludwig Institute for Cancer Research, Lausanne Branch and University of Lausanne, Ch. des Boveresses 155, Epalinges, 1066, Switzerland

    Léonardo Scarpellino, Jacques Zimmer, Philippe Guillaume, Immanuel F Luescher & Werner Held

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Correspondence to Werner Held.

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Doucey, MA., Scarpellino, L., Zimmer, J. et al. Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Nat Immunol 5, 328–336 (2004). https://doi.org/10.1038/ni1043

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