title: NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing.
abstract: Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein- and integrin signal-dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear. We experimentally controlled the availability of human ligands to regulate NK cell signaling and promote granule convergence with either directed or nondirected degranulation. By the use of acoustic trap microscopy, we generated specific effector-target cell arrangements to define the impact of the two modes of degranulation. NK cells with converged granules had greater targeted and less nonspecific "bystander" killing. Additionally, NK cells in which dynein was inhibited or integrin blocked under physiological conditions demonstrated increased nondirected degranulation and bystander killing. Thus, NK cells converge lytic granules and thereby improve the efficiency of targeted killing and prevent collateral damage to neighboring healthy cells.
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030.|Department of Pediatrics, Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Hsu
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030.|Department of Pediatrics, Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Emily M
authors.identifier: http://orcid.org/0000-0003-0226-7393
authors.initials: EM
authors.lastname: Mace
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030.|Department of Pediatrics, Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Alexandre F
authors.identifier: http://orcid.org/0000-0003-1326-2205
authors.initials: AF
authors.lastname: Carisey
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030.|Rice University, Houston, TX 77005.
authors.forename: Dixita I
authors.initials: DI
authors.lastname: Viswanath
authors.affiliation: Department of Applied Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.
authors.forename: Athanasia E
authors.identifier: http://orcid.org/0000-0002-3139-1724
authors.initials: AE
authors.lastname: Christakou
authors.affiliation: Department of Applied Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-3247-1945
authors.initials: M
authors.lastname: Wiklund
authors.affiliation: Department of Applied Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Önfelt
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030 orange@bcm.edu.|Department of Pediatrics, Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.|Rice University, Houston, TX 77005.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
mesh_terms: D024201:Bystander Effect / Q000187:drug effects; D015550:Cell Degranulation; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D052999:Quinazolinones; D017452:Receptors, IgG; C000595851:ciliobrevin D