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2014 ; 193
(12
): 5809-15
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Polarized granzyme release is required for antigen-driven transendothelial
migration of human effector memory CD4 T cells
#MMPMID25367116
Manes TD
; Pober JS
J Immunol
2014[Dec]; 193
(12
): 5809-15
PMID25367116
show ga
Human effector memory CD4 T cells may transmigrate across endothelial cell (EC)
monolayers either in response to inflammatory chemokines or in response to TCR
recognition of Ag presented on the surface of the EC. The kinetics, morphologic
manifestations, and molecular requirements of chemokine- and TCR-driven
transendothelial migration (TEM) differ significantly. In this study, we report
that, whereas the microtubule organizing center (MTOC) and cytosolic granules
follow the nucleus across the endothelium in a uropod during chemokine-driven
TEM, MTOC reorientation to the contact region between the T cell and the EC,
accompanied by dynein-driven transport of granzyme-containing granules to and
exocytosis at the contact region, are early events in TCR-driven, but not
chemokine-driven TEM. Inhibitors of either granule function or granzyme
proteolytic activity can arrest TCR-driven TEM, implying a requirement for
granule discharge in the process. In the final stages of TCR-driven TEM, the MTOC
precedes, rather than follows, the nucleus across the endothelium. Thus,
TCR-driven TEM of effector memory CD4 T cells appears to be a novel process that
more closely resembles immune synapse formation than it does conventional
chemotaxis.