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

Peilin Zheng, Lenora M. Noroski, Imelda C. Hanson, Yuhui Chen, Michelle E. Lee, Yu Huang, Michael X. Zhu, Pinaki P. Banerjee, George Makedonas, Jordan S. Orange, William T. Shearer, Dongfang Liu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1293-1302
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume135
Issue number5
DOIs
StatePublished - May 2015

Keywords

  • CrkL
  • functional natural killer deficiency
  • immunological synapse
  • natural killer cells
  • partial DiGeorge syndrome
  • β-integrin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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