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Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against... Full description

Journal Title: The Journal of allergy and clinical immunology March 2013, Vol.131(3), pp.840-8
Main Author: Mizesko, Melissa C
Other Authors: Banerjee, Pinaki P , Monaco-Shawver, Linda , Mace, Emily M , Bernal, William E , Sawalle-Belohradsky, Julie , Belohradsky, Bernd H , Heinz, Valerie , Freeman, Alexandra F , Sullivan, Kathleen E , Holland, Steven M , Torgerson, Troy R , Al-Herz, Waleed , Chou, Janet , Hanson, Imelda C , Albert, Michael H , Geha, Raif S , Renner, Ellen D , Orange, Jordan S
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1097-6825 ; PMID: 23380217 Version:1 ; DOI: 10.1016/j.jaci.2012.12.1568
Link: http://pubmed.gov/23380217
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title: Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
format: Article
creator:
  • Mizesko, Melissa C
  • Banerjee, Pinaki P
  • Monaco-Shawver, Linda
  • Mace, Emily M
  • Bernal, William E
  • Sawalle-Belohradsky, Julie
  • Belohradsky, Bernd H
  • Heinz, Valerie
  • Freeman, Alexandra F
  • Sullivan, Kathleen E
  • Holland, Steven M
  • Torgerson, Troy R
  • Al-Herz, Waleed
  • Chou, Janet
  • Hanson, Imelda C
  • Albert, Michael H
  • Geha, Raif S
  • Renner, Ellen D
  • Orange, Jordan S
subjects:
  • Actins -- Immunology
  • Guanine Nucleotide Exchange Factors -- Deficiency
  • Immunologic Deficiency Syndromes -- Immunology
  • Killer Cells, Natural -- Immunology
ispartof: The Journal of allergy and clinical immunology, March 2013, Vol.131(3), pp.840-8
description: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.
language: eng
source:
identifier: E-ISSN: 1097-6825 ; PMID: 23380217 Version:1 ; DOI: 10.1016/j.jaci.2012.12.1568
fulltext: fulltext
issn:
  • 10976825
  • 1097-6825
url: Link


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titleDefective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
creatorMizesko, Melissa C ; Banerjee, Pinaki P ; Monaco-Shawver, Linda ; Mace, Emily M ; Bernal, William E ; Sawalle-Belohradsky, Julie ; Belohradsky, Bernd H ; Heinz, Valerie ; Freeman, Alexandra F ; Sullivan, Kathleen E ; Holland, Steven M ; Torgerson, Troy R ; Al-Herz, Waleed ; Chou, Janet ; Hanson, Imelda C ; Albert, Michael H ; Geha, Raif S ; Renner, Ellen D ; Orange, Jordan S
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subjectActins -- Immunology ; Guanine Nucleotide Exchange Factors -- Deficiency ; Immunologic Deficiency Syndromes -- Immunology ; Killer Cells, Natural -- Immunology
descriptionDedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.
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titleDefective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
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0Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear.
1We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency.
2A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured.
3DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content.
4DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.
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titleDefective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
authorMizesko, Melissa C ; Banerjee, Pinaki P ; Monaco-Shawver, Linda ; Mace, Emily M ; Bernal, William E ; Sawalle-Belohradsky, Julie ; Belohradsky, Bernd H ; Heinz, Valerie ; Freeman, Alexandra F ; Sullivan, Kathleen E ; Holland, Steven M ; Torgerson, Troy R ; Al-Herz, Waleed ; Chou, Janet ; Hanson, Imelda C ; Albert, Michael H ; Geha, Raif S ; Renner, Ellen D ; Orange, Jordan S
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abstractDedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear.
doi10.1016/j.jaci.2012.12.1568
pmid23380217
date2013-03