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.
Lack of DOCK8 impairs the primary biologic functions of human NK cells and abrogates CCR7 surface expression in a WASP-independent manner
Patrizi O.;Gazzurelli L.;Rezzola S.;Plebani A.;Badolato R.;Parolini S.;Lougaris V.;Tabellini G.
2022-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
