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 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.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We wish to thank Claire Hivroz for critical reading of the manuscript and Vincenzo Sorrentino for useful advice.
Funding
This work was carried out with the support of Fondazione Telethon, Italy (Grant GGP16003) to CTB. The support of ERC Synergy (grant 951329) to CTB is also acknowledged.
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NC, AO, FF, CC, and CTB designed research and analyzed and interpreted data; NC, AO, FF, CC, JB, AT, and CDB carried out the experiments; AP, SDE, MB, LG, DDB, MMD, and VL contributed vital reagents; NC and CTB drafted the manuscript.
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Experiments were performed after approval by the institutional review board of the Universities of Florence and Brescia. Peripheral blood was obtained after informed consent according to the Declaration of Helsinki, and sample size was kept small according to the guidelines of the ethics committee.
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Capitani, N., Onnis, A., Finetti, F. et al. A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly. Cell Death Differ 29, 65–81 (2022). https://doi.org/10.1038/s41418-021-00837-5
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DOI: https://doi.org/10.1038/s41418-021-00837-5
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