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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 7

Absence of ARPC1B alters surface expression of CD8 and GLUT1 in hCTLs.

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Absence of ARPC1B alters surface expression of CD8 and GLUT1 in hCTLs.
(...
(A–D) HD and ARPC1B-deficient patient hCTLs were fixed in PFA for 20 minutes, permeabilized, and stained with an antibody against CD8 alone (green) (A and B) or in combination with anti-GLUT1 (red) and anti-EEA1 (white) antibodies (C and D). Images are 3D reconstructions of Z-stack. Scale bars: 4 μm. (E) Measurement of the mean intensity of GLUT1 expressed in AU and the degree of colocalization with EEA1 expressed as PCC (see Methods) in HD and ARPC1B-deficient patient hCTLs based on images as sampled in C and D. HD, n = 41 cells; ARPC1B-deficient patient, n = 38 cells. P < 0.005 (unpaired t test). **P < 0.0013; ***P < 0.0002. (F) Flow cytometry analysis of the proliferation capacity of HD and ARPC1B-deficient patient hCTLs (gated on live CD8+ cells) in the absence (blue) or presence (red) of plate-bound anti-CD3 stimulation (1 μg/mL). All data are representative of 3 independent experiments.
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