Journal
JOURNAL OF CELL BIOLOGY
Volume 220, Issue 10, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202104093
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- Wellcome Trust
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Cytotoxic T lymphocytes (CTLs) play a crucial role in killing viruses and cancer cells with high precision. The pathways orchestrating killing within CTLs remain consistent regardless of signal strength, but the initiation rate along these pathways varies with signal strength.
Cytotoxic T lymphocytes (CTLs) are key effector cells in the immune response against viruses and cancers, killing targets with high precision. Target cell recognition by CTL triggers rapid polarization of intracellular organelles toward the synapse formed with the target cell, delivering cytolytic granules to the immune synapse. Single amino acid changes within peptides binding MHC class I (pMHCs) are sufficient to modulate the degree of killing, but exactly how this impacts the choreography of centrosome polarization and granule delivery to the target cell remains poorly characterized. Here we use 4D imaging and find that the pathways orchestrating killing within CTL are conserved irrespective of the signal strength. However, the rate of initiation along these pathways varies with signal strength. We find that increased strength of signal leads to an increased proportion of CTLs with prolonged dwell times, initial Ca2+ fluxes, centrosome docking, and granule polarization. Hence, TCR signal strength modulates the rate but not organization of effector CTL responses.
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