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

is a key factor for the assembly and maintenance of the complex that is involved in actin branching from an existing filament. Germline biallelic mutations in 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 duanyu37C1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in duanyu37C1B 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 duanyu37C1B 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. T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of duanyu37C1B in patients' T cells using a lentiviral vector restored both duanyu37C1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored duanyu37C1B 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 duanyu37C1B displayed improved T-cell migration. Inherited duanyu37C1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.

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