A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly

Nagaja Capitani, Anna Onnis, Francesca Finetti, Chiara Cassioli, Alessandro Plebani, Jlenia Brunetti, Arianna Troilo, Sofia D’Elios, Manuela Baronio, Luisa Gazzurelli, Chiara Della Bella, Daniel D. Billadeau, Mario Milco D’Elios, Vassilios Lougaris, Cosima T. Baldari

Research output: Contribution to journalArticlepeer-review


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 211 C > T 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.

Original languageEnglish (US)
Pages (from-to)65-81
Number of pages17
JournalCell Death and Differentiation
Issue number1
StatePublished - Jan 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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