title: Loss of kindlin-3 alters the threshold for NK cell activation in human leukocyte adhesion deficiency-III.
abstract: Recent evidence suggests that kindlin-3 is a major coactivator, required for most, if not all, integrin activities. Here we studied the function of kindlin-3 in regulating NK cell activation by studying a patient with kindlin-3 deficiency (leukocyte adhesion deficiency-III). We found that kindlin-3 is required for NK cell migration and adhesion under shear force. Surprisingly, we also found that kindlin-3 lowers the threshold for NK cell activation. Loss of kindlin-3 has a pronounced effect on NK cell-mediated cytotoxicity triggered by single activating receptors. In contrast, for activation through multiple receptors, kindlin-3 deficiency is overcome and target cells killed. The realization that NK cell activity is impaired, but not absent in leukocyte adhesion deficiency, may lead to the development of more efficient therapy for this rare disease.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Institute for Medical Research Israel-Canada, Jerusalem, Israel.
authors.forename: Raizy
authors.initials: R
authors.lastname: Gruda
authors.forename: Alice C N
authors.initials: AC
authors.lastname: Brown
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Saar
authors.initials: S
authors.lastname: Mizrahi
authors.forename: Chamutal
authors.initials: C
authors.lastname: Gur
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Hagit
authors.initials: H
authors.lastname: Achdout
authors.forename: Yotam
authors.initials: Y
authors.lastname: Bar-On
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018388:Codon, Terminator; D003602:Cytotoxicity, Immunologic; D005838:Genotype; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D055503:Protein Multimerization; D021381:Protein Transport; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000276:immunology / Q000378:metabolism; D033081:Shear Strength
chemical_list: D000199:Actins; D018388:Codon, Terminator; C477322:FERMT3 protein, human; C527085:KLRK1 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D017452:Receptors, IgG; D055607:Receptors, Natural Killer Cell