title: The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.
abstract: NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice) is prominent. We have recently demonstrated that in type 1 diabetes (T1D) NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D) using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, The Department of Immunology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Chamutal
authors.initials: C
authors.lastname: Gur
authors.forename: Jonatan
authors.initials: J
authors.lastname: Enk
authors.forename: Efraim
authors.initials: E
authors.lastname: Weitman
authors.forename: Etty
authors.initials: E
authors.lastname: Bachar
authors.forename: Yaron
authors.initials: Y
authors.lastname: Suissa
authors.forename: Guy
authors.initials: G
authors.lastname: Cohen
authors.forename: Rachel Ben-Haroush
authors.initials: RB
authors.lastname: Schyr
authors.forename: Helena
authors.initials: H
authors.lastname: Sabanay
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Ariel
authors.initials: A
authors.lastname: Pribluda
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Hanna
authors.forename: Gill
authors.initials: G
authors.lastname: Leibowitz
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage; D008024:Ligands; D008297:Male; D051379:Mice; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000950:Antigens, Ly; D007328:Insulin; D020738:Leptin; D008024:Ligands; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse