title: Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human natural killer cells.
abstract: It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions.
authors.affiliation: Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom.
authors.forename: Karsten
authors.initials: K
authors.lastname: Köhler
authors.forename: Shiqiu
authors.initials: S
authors.lastname: Xiong
authors.forename: Joanna
authors.initials: J
authors.lastname: Brzostek
authors.forename: Maryam
authors.initials: M
authors.lastname: Mehrabi
authors.forename: Philipp
authors.initials: P
authors.lastname: Eissmann
authors.forename: Alice
authors.initials: A
authors.lastname: Harrison
authors.forename: Shaun-Paul
authors.initials: SP
authors.lastname: Cordoba
authors.forename: Stephane
authors.initials: S
authors.lastname: Oddos
authors.forename: Vladimir
authors.initials: V
authors.lastname: Miloserdov
authors.forename: Keith
authors.initials: K
authors.lastname: Gould
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Burroughs
authors.forename: Philip Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054342:Receptors, KIR2DL1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; C093100:KIR2DL1 protein, human; C527085:KLRK1 protein, human; D008024:Ligands; D008164:Luminescent Proteins; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054342:Receptors, KIR2DL1; D011993:Recombinant Fusion Proteins