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Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity
Lyra O. Randzavola, … , Taco W. Kuijpers, Gillian M. Griffiths
Lyra O. Randzavola, … , Taco W. Kuijpers, Gillian M. Griffiths
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5600-5614. https://doi.org/10.1172/JCI129388.
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Research Article Cell biology Immunology

Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity

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Abstract

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.

Authors

Lyra O. Randzavola, Katharina Strege, Marie Juzans, Yukako Asano, Jane C. Stinchcombe, Christian M. Gawden-Bone, Matthew N.J. Seaman, Taco W. Kuijpers, Gillian M. Griffiths

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Figure 5

Electron and light microscopy reveal atypical synapse formation by ARPC1B-deficient hCTLs.

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Electron and light microscopy reveal atypical synapse formation by ARPC1...
(A) Electron micrograph of HD and ARPC1B patient hCTLs conjugated to P815 target cells (false colored in blue) for 25 minutes. (B) hCTLs from HD and ARPC1B-deficient patient were conjugated to blue P815 target cells, fixed, and labeled with anti-CD8 (green) and anti-ARPC1B (red) antibodies and phalloidin (white). 3D reconstructions of Z-stack are shown. Scale bars: 3 μm. Data are representative of 3 independent experiments (A and B). (C) Actin dynamics in HD and ARPC1B-deficient patient hCTLs expressing mApple-Lifeact (red) during interaction with blue P815 target cells. Images are single confocal slice from Video 3 at the indicated time points (min:s) from the first contact. Data are representative of 5 independent experiments. Scale bars: 5 μm.
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