title: Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Baylor College of Medicine, Houston, TX 77030-2399, USA.
authors: Melissa C
authors: MC
authors: Mizesko
authors: Pinaki P
authors: PP
authors: Banerjee
authors: Linda
authors: L
authors: Monaco-Shawver
authors: Emily M
authors: EM
authors: Mace
authors: William E
authors: WE
authors: Bernal
authors: Julie
authors: J
authors: Sawalle-Belohradsky
authors: Bernd H
authors: BH
authors: Belohradsky
authors: Valerie
authors: V
authors: Heinz
authors: Alexandra F
authors: AF
authors: Freeman
authors: Kathleen E
authors: KE
authors: Sullivan
authors: Steven M
authors: SM
authors: Holland
authors: Troy R
authors: TR
authors: Torgerson
authors: Waleed
authors: W
authors: Al-Herz
authors: Janet
authors: J
authors: Chou
authors: Imelda C
authors: IC
authors: Hanson
authors: Michael H
authors: MH
authors: Albert
authors: Raif S
authors: RS
authors: Geha
authors: Ellen D
authors: ED
authors: Renner
authors: Jordan S
authors: JS
authors: Orange
mesh_terms: D000199:Actins / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D007223:Infant; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male
chemical_list: D000199:Actins; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors
references: J Pediatr. 2004 Jan;144(1):93-9
references: 14722525
references: Eur J Immunol. 2011 Dec;41(12):3423-35
references: 21969276
references: Blood. 2010 Apr 8;115(14):2818-26
references: 20130240
references: Clin Immunol. 2012 Jun;143(3):266-72
references: 22534316
references: Blood. 2011 Nov 24;118(22):5862-71
references: 22123909
references: Microbes Infect. 2002 Dec;4(15):1545-58
references: 12505527
references: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11351-6
references: 12177428
references: Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11912-7
references: 20547841
references: J Immunol. 2006 Aug 1;177(3):1708-20
references: 16849480
references: Curr Opin Pediatr. 2011 Dec;23(6):653-8
references: 21970826
references: Dis Markers. 2010;29(3-4):123-30
references: 21178271
references: J Allergy Clin Immunol. 2011 Aug;128(2):420-22.e2
references: 21546070
references: J Pediatr. 1997 Mar;130(3):388-93
references: 9063413
references: J Innate Immun. 2011;3(3):213-5
references: 21454963
references: Dis Markers. 2010;29(3-4):141-50
references: 21178273
references: J Immunol Methods. 2010 Apr 15;355(1-2):1-13
references: 20171970
references: FEBS Lett. 2004 Aug 13;572(1-3):159-66
references: 15304341
references: N Engl J Med. 2009 Nov 19;361(21):2046-55
references: 19776401
references: J Clin Invest. 2011 Apr;121(4):1535-48
references: 21383498
references: J Allergy Clin Immunol. 2009 Dec;124(6):1289-302.e4
references: 20004785
references: Nat Immunol. 2012 May 13;13(6):612-20
references: 22581261
references: Blood. 2004 Jul 15;104(2):436-43
references: 15001467
references: Nat Immunol. 2009 Dec;10(12):1283-91
references: 19898472
references: Immunity. 2007 Jun;26(6):798-811
references: 17540585
references: Arch Dermatol. 2012 Jan;148(1):79-84
references: 21931011
references: J Exp Med. 2011 Oct 24;208(11):2305-20
references: 22006977
references: J Cell Sci. 2002 Dec 15;115(Pt 24):4901-13
references: 12432077
references: J Allergy Clin Immunol. 2010 Dec;126(6):1304-5.e3
references: 20810158
references: Proc Natl Acad Sci U S A. 1995 May 23;92(11):5027-31
references: 7761442
references: J Immunol. 2009 Jun 1;182(11):6969-84
references: 19454694
references: Cell Res. 2006 Jan;16(1):20-4
references: 16467872
references: Mol Biol Cell. 1997 Feb;8(2):341-51
references: 9190212
references: Klin Padiatr. 2010 Nov;222(6):351-5
references: 21058221
references: Blood. 2012 May 10;119(19):4451-61
references: 22461490
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14151-6
references: 14612578
references: J Exp Med. 2007 Oct 1;204(10):2305-20
references: 17785506
references: J Innate Immun. 2011;3(4):327-8
references: 21613776
references: Curr Opin Allergy Clin Immunol. 2006 Dec;6(6):399-409
references: 17088643