T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency

I Brigida, M Zoccolillo, MP Cicalese, L Pfajfer, Federica Barzaghi, S Scala, C Oleaga-Quintas, JA Álvarez-Álvarez, L Sereni, S Giannelli, C Sartirana, F Dionisio, L Pavesi, M Benavides-Nieto, L Basso-Ricci, P Capasso, Benedetta Mazzi, J Rosain, N Marcus, YN LeeR Somech, M Degano, G Raiola, R Caorsi, P Picco, MM Velez, J Khourieh, AA Arias, A Bousfiha, T Issekutz, A Issekutz, B Boisson, K Dobbs, A Villa, A Lombardo, B Neven, D Moshous, JL Casanova, JL Franco, LD Notarangelo, C Scielzo, S Volpi, L Dupré, J Bustamante, M Gattorno, A Aiuti

Research output: Contribution to journalArticlepeer-review


ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-a2directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD81 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. © 2018 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)2362-2374
Number of pages13
Issue number22
Publication statusPublished - 2018


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