Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses.
Cytotoxic lymphocytes kill target cells by releasing the content of secretory lysosomes at the immune synapse. To understand the dynamics and control of cytotoxic immune synapses, we imaged human primary, live natural killer cells on lipid bilayers carrying ligands of activation receptors. Formation of an organized synapse was dependent on the presence of the beta2 integrin ligand ICAM-1. Ligands of coactivation receptors 2B4 and NKG2D segregated into central and peripheral regions, respectively. Lysosomal protein LAMP-1 that was exocytosed during degranulation accumulated in a large and spatially stable cluster, which overlapped with a site of membrane internalization. Lysosomal compartments reached the plasma membrane at focal points adjacent to centrally accumulated LAMP-1. Imaging of fixed cells revealed that perforin-containing granules were juxtaposed to an intracellular compartment where exocytosed LAMP-1 was retrieved. Thus, cytotoxic immune synapses include a central region of bidirectional vesicular traffic, which is controlled by integrin signaling.
Liu
Dongfang
D
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Bryceson
Yenan T
YT
Meckel
Tobias
T
Vasiliver-Shamis
Gaia
G
Dustin
Michael L
ML
Long
Eric O
EO
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D022161:Transport Vesicles / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1
D015703:Antigens, CD; D018821:CD18 Antigens; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D051907:Lysosomal Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054353:Perforin; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; C084093:CD244 protein, human; C527085:KLRK1 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1