Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity

• Published in: The Journal of clinical investigation Vol. 129; no. 12; pp. 5600 - 5614
• Main Authors: Randzavola, Lyra O, Strege, Katharina, Juzans, Marie, Asano, Yukako, Stinchcombe, Jane C, Gawden-Bone, Christian M, Seaman, Matthew Nj, Kuijpers, Taco W, Griffiths, Gillian M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-12-2019
• Subjects: Actin; Actin-Related Protein 2-3 Complex - analysis; Actin-Related Protein 2-3 Complex - physiology; Actins - analysis; Antigens; B cells; Biochemistry; CD8 Antigens - analysis; Cell death; Cell membranes; Cell Polarity; Cytotoxicity, Immunologic; Disease susceptibility; Glucose Transporter Type 1 - analysis; Health aspects; HEK293 Cells; Humans; Immune response; Immunodeficiency; Immunological Synapses - physiology; Infection; Lymphocyte Activation; Lymphocytes; Medical equipment industry; Membrane proteins; Muscle proteins; Proteins; Receptors, Antigen, T-Cell, alpha-beta - analysis; Recurrence (Disease); T cells; T-Lymphocytes, Cytotoxic - immunology; Virus diseases; United States; United Kingdom; Cytoskeleton; Adaptive immunity; Immunology; T cells; Cell Biology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI129388

CD8 cytotoxic T lymphocytes (CTLs) rely on rapid reorganization of the branched F-actin network to drive the polarized secretion of lytic granules, initiating target cell death during the adaptive immune response. Branched F-actin is generated by the nucleation factor actin-related protein 2/3 (Arp2/3) complex. Patients with mutations in the actin-related protein complex 1B (ARPC1B) subunit of Arp2/3 show combined immunodeficiency, with symptoms of immune dysregulation, including recurrent viral infections and reduced CD8+ T cell count. Here, we show that loss of ARPC1B led to loss of CTL cytotoxicity, with the defect arising at 2 different levels. First, ARPC1B is required for lamellipodia formation, cell migration, and actin reorganization across the immune synapse. Second, we found that ARPC1B is indispensable for the maintenance of TCR, CD8, and GLUT1 membrane proteins at the plasma membrane of CTLs, as recycling via the retromer and WASH complexes was impaired in the absence of ARPC1B. Loss of TCR, CD8, and GLUT1 gave rise to defects in T cell signaling and proliferation upon antigen stimulation of ARPC1B-deficient CTLs, leading to a progressive loss of CD8+ T cells. This triggered an activation-induced immunodeficiency of CTL activity in ARPC1B-deficient patients, which could explain the susceptibility to severe and prolonged viral infections.