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Blood. 2018 Nov 29;132(22):2362-2374. doi: 10.1182/blood-2018-07-863431. Epub 2018 Sep 25.

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

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San Raffaele Telethon Institute for Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
Department of Systems Medicine, Tor Vergata University, Rome, Italy.
Pediatric Immunohematology, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
Vita-Salute San Raffaele University, Milan, Italy.
INSERM, Unité Mixte de Recherche (UMR) 1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Centre national de la recherche scientifique, UMR5282, Toulouse, France.
Université Toulouse III Paul-Sabatier, Toulouse, France.
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Paris Descartes University, Imagine Institute, Paris, France.
Group of Primary Immunodeficiencies, Department of Microbiology & Parasitology, School of Medicine, University of Antioquia (UdeA), Medellín, Colombia.
IPS Universitaria, Health Services of University of Antioquia, Medellín, Colombia.
Division of Experimental Oncology, Unit of B-Cell Neoplasia, San Raffaele Scientific Institute, Milan, Italy.
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Genome Dynamics in the Immune System, Université Paris Descartes-Sorbonne Paris, Paris, France.
Immunogenetics Laboratory, HLA & Chimerism, Department of Immunohematology & Blood Transfusion, IRCCS Ospedale San Raffaele, Milano, Italy.
Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
Kipper Institute for Allergy and Immunology, Schneider Children's Medical Center of Israel, Petach Tikva, affiliated with Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Pediatric Department A and the Immunology Services, "Edmond and Lily Safra" Children's Hospital, Jeffrey Modell Foundation Center, Sheba Medical Center, Tel Hashomer, affiliated with Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Division of Immunology, Transplantation, and Infectious Diseases, Biocrystallography Unit, San Raffaele Scientific Institute, Milan, Italy.
Unità Operativa Complessa di Pediatria, Azienda Ospedaliera "Pugliese-Ciaccio" di Catanzaro.
Unità Operativa Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy.
School of Microbiology, University of Antioquia (UdeA), Medellín, Colombia.
Clinical Immunology Unit, Department of Pediatrics, King Hassan II University, Ibn-Rochd Hospital, Casablanca, Morocco.
Department of Pediatrics & Department of Microbiology-Immunology, Dalhousie University, Halifax, NS, Canada.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Milan Unit, Milan, Italy.
Howard Hughes Medical Institute, New York, NY.
Università degli Studi di Genova, Genova, Italy.
Unità Operativa Semplice Dipartimentale Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.


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-α-directed 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 CD8+ 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.

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