title: Recognition and killing of human and murine pancreatic beta cells by the NK receptor NKp46.
abstract: Type 1 diabetes is an incurable disease that is currently treated by insulin injections or in rare cases by islet transplantation. We have recently shown that NKp46, a major killer receptor expressed by NK cells, recognizes an unknown ligand expressed by β cells and that in the absence of NKp46, or when its activity is blocked, diabetes development is inhibited. In this study, we investigate whether NKp46 is involved in the killing of human β cells that are intended to be used for transplantation, and we also thoroughly characterize the interaction between NKp46 and its human and mouse β cell ligands. We show that human β cells express an unknown ligand for NKp46 and are killed in an NKp46-dependent manner. We further demonstrate that the expression of the NKp46 ligand is detected on human β cells already at the embryonic stage and that it appears on murine β cells only following birth. Because the NKp46 ligand is detected on healthy β cells, we wondered why type 1 diabetes does not develop in all individuals and show that NK cells are absent from the vicinity of islets of healthy mice and are detected in situ in proximity with β cells in NOD mice. We also investigate the molecular mechanisms controlling NKp46 interactions with its β cell ligand and demonstrate that the recognition is confined to the membrane proximal domain and stalk region of NKp46 and that two glycosylated residues of NKp46, Thr(125) and Asn(216), are critical for this recognition.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Chamutal
authors.initials: C
authors.lastname: Gur
authors.forename: Jonatan
authors.initials: J
authors.lastname: Enk
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Kassem
authors.forename: Yaron
authors.initials: Y
authors.lastname: Suissa
authors.forename: Judith
authors.initials: J
authors.lastname: Magenheim
authors.forename: Miri
authors.initials: M
authors.lastname: Stolovich-Rain
authors.forename: Tomer
authors.initials: T
authors.lastname: Nir
authors.forename: Hagit
authors.initials: H
authors.lastname: Achdout
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: James
authors.initials: J
authors.lastname: Shapiro
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Naparstek
authors.forename: Angel
authors.initials: A
authors.lastname: Porgador
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000818:Animals; D001665:Binding Sites; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D008024:Ligands; D055627:Natural Cytotoxicity Triggering Receptor 1