Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome.
J Allergy Clin Immunol
; 135(5): 1293-302, 2015 May.
Article
en En
| MEDLINE
| ID: mdl-25748067
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 ß2-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 ß2-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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Asesinas Naturales
/
Síndrome de DiGeorge
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article