T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency.
Immacolata BrigidaMatteo ZoccolilloMaria Pia CicaleseLaurène PfajferFederica BarzaghiSerena ScalaCarmen Oleaga-QuintasJesus A Álvarez-ÁlvarezLucia SereniStefania GiannelliClaudia SartiranaFrancesca DionisioLuca PavesiMarta Benavides-NietoLuca Basso-RicciPaola CapassoBenedetta MazziJeremie RosainNufar MarcusYu Nee LeeRaz SomechMassimo DeganoGiuseppe RaiolaRoberta CaorsiPaolo PiccoMarcela Moncada VelezJoelle KhouriehAndrés Augusto AriasAziz BousfihaThomas IssekutzAndrew IssekutzBertrand BoissonA Kerry DobbsAnna VillaAngelo LombardoBenedicte NevenDespina MoshousJean-Laurent CasanovaJose Luis FrancoLuigi D NotarangeloCristina ScielzoStefano VolpiLoïc DupréJacinta BustamanteMarco GattornoAlessandro AiutiPublished in: Blood (2018)
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.
Keyphrases
- early onset
- cell migration
- end stage renal disease
- poor prognosis
- cell proliferation
- ejection fraction
- chronic kidney disease
- flow cytometry
- binding protein
- regulatory t cells
- prognostic factors
- copy number
- peritoneal dialysis
- signaling pathway
- immune response
- intellectual disability
- oxidative stress
- peripheral blood
- cord blood
- single molecule
- dendritic cells
- replacement therapy