S. Franitza et al., TNF-alpha associated with extracellular matrix fibronectin provides a stopsignal for chemotactically migrating T cells, J IMMUNOL, 165(5), 2000, pp. 2738-2747
The migration of T cells into extravascular sites of inflammation is regula
ted by information derived from the molecular structure of the invaded tiss
ue and from chemokine and cytokine gradients in the context of the extracel
lular matrix (ECM). Although recent studies have highlighted the role of pa
rticular chemoattractants in leukocyte migration, to date little Is known a
bout how specific combinations of contextual signals control the migration
of leukocytes and their localization at sites of inflammation. Here me stud
ied the interplay between a pleiotropic cytokine, TNF-alpha, and two protot
ypic chemoattractants, RANTES and stromal cell-derived factor-1 alpha (SDF-
1 alpha), on human CD45RO(+) T cells migrating within an ECM-like contest,
For this purpose, we used a newly constructed three-dimensional gel system
designed to follow, in real time, the migration of individual leukocytes al
ong chemotactic gradients in vitro. We found that TNF-alpha, which binds th
e ECM protein fibronectin and lacks adhesion- and migration-promoting effec
ts of its own, can act as a proadhesive cytokine on T cells exposed to RANT
ES and SDF-1 alpha, Furthermore, fibronectin-complexed TNF-alpha provided a
nchorage signals to the T cells as they moved directionally along chemoattr
active gradients. This effect of TNF-alpha required an intact TNF-alpha rec
eptor II subtype on the migrating T cells. The anchoring effect of TNF-alph
a appears to be specific; IL-2, an integrin-activating proadhesive cytokine
, does not transmit stoppage signals to T cell migration induced by RANTES,
Thus, TNF-alpha present in the ECM at sites of inflammation may function t
o anchor T cells recruited to these sites by chemotactic signals.