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DOCK8 Drives Src-Dependent NK Cell Effector Function.

Conor J Kearney1,2, Stephin J Vervoort3, Kelly M Ramsbottom1

  • 1Immune Defence Laboratory, Cancer Immunology Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.

Journal of Immunology (Baltimore, Md. : 1950)
|August 11, 2017
PubMed
Summary
This summary is machine-generated.

Dedicator of cytokinesis 8 (DOCK8) regulates natural killer (NK) cell immune responses. DOCK8 deficiency impairs NK cell cytotoxicity and cytokine production by affecting Lck kinase activation.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause hyper-IgE syndrome, leading to immunodeficiency, infections, and malignancy.
  • DOCK8's role in natural killer (NK) cell function and immune surveillance is not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which DOCK8 regulates NK cell cytotoxicity and cytokine production.
  • To elucidate DOCK8's role in NK cell responses to target cell engagement and receptor ligation.

Main Methods:

  • Genetic ablation of DOCK8 in human NK cells.
  • Analysis of cytokine transcription and secretion.
  • Assessment of Src family kinase activation, specifically Lck.
  • Stimulation assays using target cells, NKp30 ligation, and PMA/Ionomycin.

Main Results:

  • DOCK8 deficiency attenuated NK cell cytotoxicity and cytokine production.
  • DOCK8 regulates cytokine production via inhibition of Lck activation downstream of target cell engagement or NKp30 ligation.
  • PMA/Ionomycin treatment rescued cytokine production in DOCK8-deficient NK cells, indicating a defect proximal to receptor ligation.
  • NK cells from DOCK8-deficient patients showed reduced IFN-γ and TNF-α production upon NKp30 stimulation.

Conclusions:

  • DOCK8 plays a critical role in regulating NK cell cytotoxicity and cytokine secretion.
  • DOCK8 acts through the Lck kinase pathway to control NK cell-mediated immunity.
  • This study reveals a novel mechanism for DOCK8 in NK cell function and immune surveillance.