Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Blood, 2018-11, Vol.132 (22), p.2362-2374

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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. •ARPC1B deficiency alters T-cell proliferation, cytoskeleton dynamics, cell migration, and immunological synapse assembly.•Functional defects are corrected in naturally revertant and ex vivo transduced T cells. [Display omitted]