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

Immacolata Brigida, Matteo Zoccolillo, Maria Pia Cicalese, Laurène Pfajfer, Federica Barzaghi, Serena Scala, Carmen Oleaga-Quintas, Jesus A. Álvarez-Álvarez, Lucia Sereni, Stefania Giannelli, Claudia Sartirana, Francesca Dionisio, Luca Pavesi, Marta Benavides-Nieto, Luca Basso-Ricci, Paola Capasso, Benedetta Mazzi, Jeremie Rosain, Nufar Marcus, Yu Nee LeeRaz Somech, Massimo Degano, Giuseppe Raiola, Roberta Caorsi, Paolo Picco, Marcela Moncada Velez, Joelle Khourieh, Andrés Augusto Arias, Aziz Bousfiha, Thomas Issekutz, Andrew Issekutz, Bertrand Boisson, Kerry Dobbs, Anna Villa, Angelo Lombardo, Benedicte Neven, Despina Moshous, Jean Laurent Casanova, José Luis Franco, Luigi D. Notarangelo, Cristina Scielzo, Stefano Volpi, Loïc Dupré, Jacinta Bustamante, Marco Gattorno, Alessandro Aiuti*

*Corresponding author for this work

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.

Original languageEnglish
Pages (from-to)2362-2374
Number of pages13
Issue number22
StatePublished - 29 Nov 2018


FundersFunder number
National Institute of Allergy and Infectious DiseasesZIAAI001222


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