Lack of DOCK8 impairs the primary biologic functions of human NK cells and abrogates CCR7 surface expression in a WASP-independent manner

Clin Immunol. 2022 Apr:237:108974. doi: 10.1016/j.clim.2022.108974. Epub 2022 Mar 10.

Abstract

Dedicator of Cytokinesis 8 (DOCK8) deficiency is a rare form of autosomal recessive combined immunodeficiency. The effect of DOCK8 deficiency on Natural Killer cell biology has not been fully elucidated yet. Thus, we undertook a detailed phenotypic and functional evaluation of NK cells from seven patients with DOCK8 deficiency. Patients' immature CD56bright NK cells were defective in IFN-γ secretion, while their mature CD56dim NK cells showed impaired cytotoxicity, partially rescued upon rIL-2 addition. Cross-linking of NK cell receptors revealed a specific defect in the CD3 zeta chain-dependent activation pathway in DOCK8 deficiency. Lack of DOCK8, but not of WASP, impaired CCR7 expression on human CD56bright NK cells, a critical receptor for their migration to secondary lymph nodes. Evaluation of a patient's lymph node showed a severe reduction in NK cells that showed increased intracellular expression of CCR7. Our data suggest that DOCK8 deficiency variably affects NK cell homeostasis in humans.

Keywords: C-C motif chemokine receptor 7; Dedicator of cytokinesis 8; Natural killer cells; Wiskott-Aldrich syndrome protein.

MeSH terms

  • CD56 Antigen / metabolism
  • Cytokinesis*
  • Guanine Nucleotide Exchange Factors* / genetics
  • Guanine Nucleotide Exchange Factors* / metabolism
  • Humans
  • Killer Cells, Natural* / metabolism
  • Receptors, CCR7* / genetics
  • Receptors, CCR7* / metabolism
  • Wiskott-Aldrich Syndrome Protein

Substances

  • CCR7 protein, human
  • CD56 Antigen
  • DOCK8 protein, human
  • Guanine Nucleotide Exchange Factors
  • Receptors, CCR7
  • WAS protein, human
  • Wiskott-Aldrich Syndrome Protein