loss of arpc1b impairs cytotoxic t lymphocyte maintenance and cytolytic activity
Cytotoxicity, Immunologic
Cytotoxic
IMMUNOLOGICAL SYNAPSE
Immunological Synapses
Cytotoxicity
T-Lymphocytes
Receptors, Antigen, T-Cell, alpha-beta
Research & Experimental Medicine
Lymphocyte Activation
ARP2/3 COMPLEX
GLUCOSE
ACTIVATION
immunology
Immunologic
Receptors
BINDING
RETROMER
11 Medical and Health Sciences
Cytoskeleton
alpha-beta
Glucose Transporter Type 1
0303 health sciences
Research & Experimental
Cell Polarity
adaptive immunity
FAM21
3. Good health
Medicine, Research & Experimental
Antigen
Medicine
Life Sciences & Biomedicine
Research Article
570
Cell biology
CD8 Antigens
Adaptive immunity
Immunology
GRANULE SECRETION
T cells
610
Actin-Related Protein 2-3 Complex
ACTIN
03 medical and health sciences
Humans
Science & Technology
FOS: Clinical medicine
Cell Biology
T-Cell
Actins
WASH COMPLEX
HEK293 Cells
T-Lymphocytes, Cytotoxic
DOI:
10.17863/cam.46931
Publication Date:
2019-11-11
AUTHORS (9)
ABSTRACT
CD8 cytotoxic T lymphocytes (CTL) 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 Arp2/3 complex. Patients with mutations in the 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 two different levels. First ARPC1B is required for lamellipodia formation, cell migration and actin reorganisation 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 CTL, 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 signalling and proliferation upon antigen stimulation of ARPC1B-deficient CTL, 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.
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