Mauro Giacomelli1, Rajesh Kumar1, Annarosa Soresina2, Nicola Tamassia3, Tiziana Lorenzini2, Daniele Moratto2, Sara Gasperini3, Marco Cassatella3, Alessandro Plebani2, Vassilios Lougaris2, Raffaele Badolato4. 1. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy; Scuola di Dottorato in Scienze della Riproduzione e dello Sviluppo, University of Trieste, Trieste, Italy. 2. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy. 3. Pathology Department, University of Verona, Verona, Italy. 4. Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy. Electronic address: raffaele.badolato@unibs.it.
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.
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.
Authors: Ana I Sánchez; Mary A García-Acero; Angela Paredes; Rossi Quero; Rita I Ortega; Jorge A Rojas; Daniel Herrera; Miguel Parra; Karol Prieto; Juana Ángel; Luz-Stella Rodríguez; Juan C Prieto; Manuel Franco Journal: Mol Syndromol Date: 2020-02-05
Authors: Francesca B Aiello; Tad Guszczynski; Wenqing Li; Julie A Hixon; Qiong Jiang; Deborah L Hodge; Tania Massignan; Chiara Di Lisio; Anand Merchant; Antonio D Procopio; Valentina Bonetto; Scott K Durum Journal: Cell Signal Date: 2018-03-24 Impact factor: 4.315
Authors: Jérôme Mastio; Mezida B Saeed; Hannah Wurzer; Max Krecke; Lisa S Westerberg; Clément Thomas Journal: Front Immunol Date: 2020-11-09 Impact factor: 7.561