NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing

Author:

Hsu Hsiang-Ting12,Mace Emily M.12ORCID,Carisey Alexandre F.12ORCID,Viswanath Dixita I.13,Christakou Athanasia E.4ORCID,Wiklund Martin4ORCID,Önfelt Björn45,Orange Jordan S.123

Affiliation:

1. Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX 77030

2. Department of Pediatrics, Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030

3. Rice University, Houston, TX 77005

4. Department of Applied Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden

5. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden

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.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Cell Biology

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