Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome.

The Journal of Allergy and Clinical Immunology
Peilin ZhengDongfang Liu

Abstract

DiGeorge syndrome affects more than 3.5 million persons worldwide. Partial DiGeorge syndrome (pDGS), which is characterized by a number of gene deletions in chromosome 22, including the chicken tumor virus number 10 regulator of kinase (Crk)-like (CrkL) gene, is one of the most common genetic disorders in human subjects. To date, the role of natural killer (NK) cells in patients with pDGS remains unclear. We sought to define the effect of pDGS-related Crk haploinsufficiency on NK cell activation and cytotoxic immunological synapse (IS) structure and function. Inducible CrkL-silenced NK cells were used to recapitulate the pDGS, CrkL-haploinsufficient phenotype. Findings were validated by using NK cells from patients with actual pDGS. Ultimately, deficits in the function of NK cells from patients with pDGS were restored by lentiviral transduction of CrkL. Silencing of CrkL expression inhibits NK cell function. Specifically, pDGS haploinsufficiency of CrkL inhibits accumulation of activating receptors, polarization of cytolytic machinery and key signaling molecules, and activation of β2-integrin at the IS. Reintroduction of CrkL protein restores NK cell cytotoxicity. CrkL haploinsufficiency causes functional NK deficits in patient...Continue Reading

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Citations

Feb 16, 2016·The Journal of Allergy and Clinical Immunology·Mauro GiacomelliRaffaele Badolato
Nov 26, 2015·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Matthias Voss, Yenan T Bryceson
Oct 12, 2015·Immunology and Allergy Clinics of North America·Ivan K Chinn, William T Shearer
Jan 1, 2015·Nature Reviews. Disease Primers·Donna M McDonald-McGinnAnne S Bassett
Apr 6, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tsukasa NabekuraDongfang Liu
Jan 18, 2018·American Journal of Medical Genetics. Part a·Blaine CrowleyKathleen E Sullivan
Jun 9, 2019·Journal of Neurodevelopmental Disorders·Zahra MotahariAnthony-Samuel LaMantia
Dec 13, 2019·Molecular Genetics & Genomic Medicine·Catherina T PinnaroBenjamin W Darbro
Dec 20, 2018·Immunological Reviews·Emily M Mace, Jordan S Orange
Sep 25, 2020·Nature Communications·Hsiang-Chi TsengDongfang Liu
Jul 23, 2020·Molecular Therapy. Methods & Clinical Development·Yan YangDongfang Liu

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