Peilin Zheng1, Lenora M Noroski2, Imelda C Hanson2, Yuhui Chen1, Michelle E Lee3, Yu Huang4, Michael X Zhu4, Pinaki P Banerjee1, George Makedonas1, Jordan S Orange5, William T Shearer5, Dongfang Liu6. 1. Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, Houston, Tex. 2. Allergy, Immunology and Rheumatology, Texas Children's Hospital, Houston, Tex. 3. 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. 4. 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. 5. 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. 6. 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.
Abstract
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. CONCLUSION: 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.
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. CONCLUSION: 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.
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