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

Ornella Patrizi; Manuela Baronio; Luisa Gazzurelli; Stefano Rossi; Sara Rezzola; Emanuela Marcenaro; Alessandro Plebani; Raffaele Badolato; Silvia Parolini; Vassilios Lougaris; Giovanna Tabellini

doi:10.1016/j.clim.2022.108974

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.

Affiliations

¹ Department of Molecular and Translational Medicine, University of Brescia, Italy.
² Pediatrics Clinic and "A. Nocivelli" Institute for Molecular Medicine, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.
³ Department of Experimental Medicine, University of Genova, Italy.
⁴ Pediatrics Clinic and "A. Nocivelli" Institute for Molecular Medicine, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy. Electronic address: [email protected].

PMID: 35278713
DOI: 10.1016/j.clim.2022.108974

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 CD56^bright NK cells were defective in IFN-γ secretion, while their mature CD56^dim 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 CD56^bright 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