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

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complexthat 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-celllymphopenia, low numbers of naive 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 cellsto extend an actin-rich lamellipodia upon T-cellreceptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cellsadditionally displayed impaired TCR-mediated proliferation and SDF1-α−directed migration. Gene transfer of ARPC1B in patients’ T cellsusing a lentiviral vector restored both ARPC1B expression and T-cellproliferation 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 cellsexpressing normal levels of ARPC1B displayed improved T-cellmigration. Inherited ARPC1B deficiency therefore alters T-cellcytoskeletal dynamics and functions, contributing to the clinical features of CID.