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


OBJECTIVE
We sought to define the effect of pDGS-related Crk haploinsufficiency on NK cell activation and cytotoxic immunological synapse (IS) structure and function.


METHODS
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.


RESULTS
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.


CONCLUSIONS
CrkL haploinsufficiency causes functional NK deficits in patients with pDGS by disrupting both β2-integrin activation and activating receptor accumulation at the IS. Our results suggest that NK cell IS quality can directly affect immune status, providing a potential target for diagnosis and therapeutic manipulation in patients with pDGS and in other patients with functional NK cell deficiencies.
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
Peilin
P
Zheng
Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex.
Lenora M
LM
Noroski
Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex.
Imelda C
IC
Hanson
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
Yuhui
Y
Chen
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex; Wiess School of Natural Sciences, Rice University, Houston, Tex.
Michelle E
ME
Lee
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Integrative Biology and Pharmacology, Graduate Program in Cell and Regulatory Biology, University of Texas Health Science Center at Houston, Houston, Tex.
Yu
Y
Huang
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Integrative Biology and Pharmacology, Graduate Program in Cell and Regulatory Biology, University of Texas Health Science Center at Houston, Houston, Tex.
Michael X
MX
Zhu
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
Pinaki P
PP
Banerjee
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex.
George
G
Makedonas
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex.
Jordan S
JS
Orange
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex.
William T
WT
Shearer
Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex. Electronic address: dongfang.liu@bcm.edu.
Dongfang
D
Liu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D054992:Immunological Synapses / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D016023:Integrins; D009687:Nuclear Proteins; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human
CrkL; functional natural killer deficiency; immunological synapse; natural killer cells; partial DiGeorge syndrome; β(2)-integrin