title: Cutting edge: NKG2D-dependent cytotoxicity is controlled by ligand distribution in the target cell membrane.
abstract: Although the importance of membrane microdomains in receptor-mediated activation of lymphocytes has been established, much less is known about the role of receptor ligand distribution on APC and target cells. Detergent-resistant membrane domains, into which GPI-linked proteins partition, are enriched in cholesterol and glycosphingolipids. ULBP1 is a GPI-linked ligand for natural cytotoxicity receptor NKG2D. To investigate how ULBP1 distribution on target cells affects NKG2D-dependent NK cell activation, we fused the extracellular domain of ULBP1 to the transmembrane domain of CD45. Introduction of this transmembrane domain eliminated the association of ULBP1 with the detergent-resistant membrane fraction and caused a significant reduction of cytotoxicity and degranulation by NK cells. Clustering and lateral diffusion of ULBP1 was not affected by changes in the membrane anchor. These results show that the partitioning of receptor ligands in discrete membrane domains of target cells is an important determinant of NK cell activation.
authors.affiliation: Molecular and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Martinez
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Brzostowski
authors.forename: Eric O
authors.initials: EO
authors.lastname: Long
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Gross
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004058:Diffusion; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins; C423231:ULBP1 protein, human; D017493:Leukocyte Common Antigens