Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions

Abstract

Background: Partial DiGeorge syndrome (pDGS) is caused by deletion of the 22q11.2 region. Within this region lies CrK-like (CRKL), a gene encoding an adapter protein belonging to the Crk family that is involved in the signaling cascade of IL-2, stromal cell-derived factor 1α, and type I interferon. Although recurrent infections can be observed in patients with deletion of chromosome 22 syndrome, the immune pathogenesis of this condition is yet not fully understood.

Objective: We aimed to investigate the role of CRKL in T-cell functional responses in patients affected with pDGS.

Methods: Protein expression levels and phosphorylation of CRKL were evaluated in patients with pDGS. T-cell functional assays in vitro and gene-silencing experiments were also performed.

Results: CRKL protein expression, as well as its phosphorylation, were reduced in all patients with pDGS, especially on IL-2 stimulation. Moreover, T cells presented impaired proliferation and reduced IL-2 production on anti-CD3/CD28 stimulation and decreased c-Fos expression. Finally, CRKL silencing in Jurkat T cells resulted in impaired T-cell proliferation and reduced c-Fos expression.

Conclusions: The impaired T-cell proliferation and reduction of CRKL, phosphorylated CRKL, and c-Fos levels suggest a possible role of CRKL in functional deficiencies of T cells in patients with pDGS.

Keywords: CRKL; DiGeorge syndrome; IL-2; T-cell receptor activation; c-Fos; proliferation; signal transducer and activator of transcription 5.