Abstract
Understanding how cytotoxic T lymphocytes (CTLs) efficiently leave the circulation to target cancer cells or contribute to inflammation is of high medical interest. Here, we demonstrate that human central memory CTLs cross the endothelium in a predominantly paracellular fashion, whereas effector and effector memory CTLs cross the endothelium preferably in a transcellular fashion. We find that effector CTLs show a round morphology upon adhesion and induce a synapse-like interaction with the endothelium where ICAM-1 is distributed at the periphery. Moreover, the interaction of ICAM-1:β2integrin and endothelial-derived CX3CL1:CX3CR1 enables transcellular migration. Mechanistically, we find that ICAM-1 clustering recruits the SNARE-family protein SNAP23, as well as syntaxin-3 and -4, for the local release of endothelial-derived chemokines like CXCL1/8/10. In line, silencing of endothelial SNAP23 drives CTLs across the endothelium in a paracellular fashion. In conclusion, our data suggest that CTLs trigger local chemokine release from the endothelium through ICAM-1-driven signals driving transcellular migration.
Highlights
Leukocytes efficiently cross the vasculature to enter underlying tissues by migrating through the endothelial cell lining (Anderson and Anderson, 1976)
When we used real-time imaging to monitor cytotoxic T lymphocytes (CTLs) transendothelial migration (TEM) events, we found that CTL transcellular events were preceded by a depolarized phenotype, meaning that CTL either rounded up just prior to diapedesis or remained unpolarized after adhesion until transcellular transmigration and do not involve apical migration (Figures 1B and 1C)
That CTLs do not show rolling on the endothelium but after contact remain stationary and transmigrate either at the spot through the endothelial cell body or at the nearest junction that they reach by apical migration
Summary
Leukocytes efficiently cross the vasculature to enter underlying tissues by migrating through the endothelial cell lining (Anderson and Anderson, 1976). Transcellular diapedesis has been attributed to high ICAM-1 expression levels on endothelial cells (Yang et al, 2005; Gorina et al, 2014; Abadier et al, 2015). Transcellular diapedesis has been attributed to high ICAM-1 expression levels on endothelial cells (Yang et al, 2005; Gorina et al, 2014; Abadier et al, 2015), but further mechanistic details of how this route is regulated are still elusive
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