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 bi-allelic mutations in ARPC1B have been recently described in six patients with clinical features of combined immunodeficiency, 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 bi-allelic mutations in ARPC1B in six 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-IgE. 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 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 patient's T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In two of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In one 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 combined immunodeficiency.

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

Caorsi, Roberta;Volpi, Stefano;Gattorno, Marco;
2018

Abstract

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 bi-allelic mutations in ARPC1B have been recently described in six patients with clinical features of combined immunodeficiency, 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 bi-allelic mutations in ARPC1B in six 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-IgE. 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 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 patient's T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In two of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In one 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 combined immunodeficiency.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/930064
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