Citations 1
A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly
Plebani, Alessandro , Brunetti, Jlenia , Troilo, Arianna , D’Elios, Sofia , Baronio, Manuela , Gazzurrelli, Luisa, Billadeau, Daniel D. , Lougaris, Vassilios , Capitani, Nagaja , Onnis, Anna , Finetti, Francesca , Cassioli, Chiara , D’Elios, Mario Milco , Baldari, Cosima T.
No container title available | October 22, 2020 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b C211T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.