title: The Activating Human NK Cell Receptor KIR2DS2 Recognizes a β2-Microglobulin-Independent Ligand on Cancer Cells.
abstract: The functions of activating members of the killer cell Ig-like receptor (KIR) family are not fully understood, as the ligands for these receptors are largely unidentified. In this study, we report that KIR2DS2 reporter cells recognize a ligand expressed by cancer cell lines. All cancer targets recognized by KIR2DS2 were also recognized by KIR2DL2 and KIR2DL3 reporters. Trogocytosis of membrane proteins from the cancer targets was observed with responding reporter cells, indicating the formation of KIR2DS2 ligand-specific immunological synapses. HLA-C typing of target cells showed that KIR2DS2 recognition was independent of the HLA C1 or C2 group, whereas targets cells that were only recognized by KIR2DL3 expressed C1 group alleles. Anti-HLA class I Abs blocked KIR2DL3 responses toward C1-expressing targets, but they did not block KIR2DS2 recognition of cancer cells. Small interfering RNA knockdown of β2-microglobulin reduced the expression of class I H chain on the cancer targets by >97%, but it did not reduce the KIR2DS2 reporter responses, indicating a β2-microglobulin-independent ligand for KIR2DS2. Importantly, KIR2DL3 responses toward some KIR2DS2 ligand-expressing cells were also undiminished after β2-microglobulin knockdown, and they were not blocked by anti-HLA class I Abs, suggesting that KIR2DL3, in addition to the traditional HLA-C ligands, can bind to the same β2-microglobulin-independent ligand as KIR2DS2. These observations indicate the existence of a novel, presently uncharacterized ligand for the activating NK cell receptor KIR2DS2. Molecular identification of this ligand may lead to improved KIR-HLA mismatching in hematopoietic stem cell transplantation therapy for leukemia and new, more specific NK cell-based cancer therapies.
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and lavanya.thiruchelvam-kyle@medisin.uio.no.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Thiruchelvam-Kyle
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Sigurd E
authors.initials: SE
authors.lastname: Hoelsbrekken
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Per C
authors.initials: PC
authors.lastname: Saether
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Elisabeth Gyllensten
authors.initials: EG
authors.lastname: Bjørnsen
authors.affiliation: Laboratorio Immunologia, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Daniela
authors.identifier: 0000-0003-1565-451X
authors.initials: D
authors.lastname: Pende
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Sigbjørn
authors.initials: S
authors.lastname: Fossum
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Michael R
authors.identifier: 0000-0002-4128-4228
authors.initials: MR
authors.lastname: Daws
authors.affiliation: Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; and.
authors.forename: Erik
authors.identifier: 0000-0002-0216-6739
authors.initials: E
authors.lastname: Dissen
mesh_terms: D045744:Cell Line, Tumor; D002469:Cell Separation; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000378:metabolism*; D054343:Receptors, KIR2DL2 / Q000378:metabolism*
chemical_list: D008024:Ligands; D054343:Receptors, KIR2DL2