Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency - 27/02/13
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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.
Objectives |
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.
Le texte complet de cet article est disponible en PDF.Key words : DOCK8 deficiency, natural killer cells, actin, cytotoxicity, immunologic synapse
Abbreviations used : Cdc42, DOCK8, F-actin, HIES, IS, MTOC, NK, shRNA, STAT3, WAS, WASp
Plan
Supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grant R01067946 (to J.S.O.), the German Research Foundation (DFG RE2799/3-1) and a Fritz-Thyssen research foundation grant (Az. 10.07.1.159; to E.D.R.); and the Dubai-Harvard Foundation of Medical Research, the Jeffrey Modell Foundation, “Role of TACI Mutations in CVID,” 5P01AI076210-04, NIH, and “Combined SNP analysis and whole genome sequencing to discover immunodeficiency genes,” 5R03AI094017-02, NIH (to R.S.G.). |
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Disclosure of potential conflict of interest: M. C. Mizesko has received grants from the National Institutes of Health (NIH). L. Monaco-Shawver has received grants from the NIH. T. R. Torgerson has consulted for Baxter Biosciences; has grants/grants pending from Baxter Biosciences and CSL Behring; has received payment for lectures, including service on speakers’ bureaus for Baxter Biosciences; has received royalties from New England Biolabs; and has received payment for development of Educational Presentations from Baxter Biosciences. J. Chou is employed by Boston Children’s Hospital and has grants/grants pending from the NIH. R. S. Geha has received grants from the NIH. E. D. Renner has received grant money from DFG and the Fritz-Thyssen Foundation. J. S. Orange has received grants from the NIH; has consulted for Baxter Biosciences on lg therapies, CSL Bhering on lg therapies, Grifols on lg therapies, Octapharma USA on the Grants Review Committee, Cangene on lg therapy, and IBT reference laboratories on immunology; has received payment for lectures, including service on speakers’ bureaus for Baxter Healthcare; has received royalties from Unimed Publishers for a book on immunoglobulins; and has received payment for development of educational presentations from CSL Bhering for a presentation on lg therapy. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 3
P. 840-848 - mars 2013 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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