Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2019-12-02
Date Acceptance
2019-09-10
Citation
Journal of Clinical Investigation, 2019, 129 (12), pp.5600-5614
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
5600
End Page
5614
Journal / Book Title
Journal of Clinical Investigation
Volume
129
Issue
12
Copyright Statement
© 2019 Randzavola et al. This is an open access article published under
the terms of the Creative Commons Attribution 4.0 International License
the terms of the Creative Commons Attribution 4.0 International License
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000500567600047&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
ARP2/3 COMPLEX
WASH COMPLEX
IMMUNOLOGICAL SYNAPSE
GRANULE SECRETION
ACTIN
RETROMER
ACTIVATION
GLUCOSE
BINDING
FAM21
Publication Status
Published
Date Publish Online
2019-11-11