TY - JOUR
T1 - Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome
AU - Zheng, Peilin
AU - Noroski, Lenora M.
AU - Hanson, Imelda C.
AU - Chen, Yuhui
AU - Lee, Michelle E.
AU - Huang, Yu
AU - Zhu, Michael X.
AU - Banerjee, Pinaki P.
AU - Makedonas, George
AU - Orange, Jordan S.
AU - Shearer, William T.
AU - Liu, Dongfang
N1 - Publisher Copyright:
© 2015 American Academy of Allergy, Asthma & Immunology.
PY - 2015/5
Y1 - 2015/5
N2 - 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.
AB - 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.
KW - CrkL
KW - functional natural killer deficiency
KW - immunological synapse
KW - natural killer cells
KW - partial DiGeorge syndrome
KW - β-integrin
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U2 - 10.1016/j.jaci.2015.01.011
DO - 10.1016/j.jaci.2015.01.011
M3 - Article
C2 - 25748067
AN - SCOPUS:84943775491
SN - 0091-6749
VL - 135
SP - 1293
EP - 1302
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 5
ER -