The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion
Mark H. Siegelman, … , Diana Stanescu, Pila Estess
Mark H. Siegelman, … , Diana Stanescu, Pila Estess
Published March 1, 2000
Citation Information: J Clin Invest. 2000;105(5):683-691. https://doi.org/10.1172/JCI8692.
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Article

The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion

Abstract

Leukocytes extravasate from the blood in response to physiologic or pathologic demands by means of complementary ligand interactions between leukocytes and endothelial cells. The multistep model of leukocyte extravasation involves an initial transient interaction (“rolling” adhesion), followed by secondary (firm) adhesion. We recently showed that binding of CD44 on activated T lymphocytes to endothelial hyaluronan (HA) mediates a primary adhesive interaction under shear stress, permitting extravasation at sites of inflammation. The mechanism for subsequent firm adhesion has not been elucidated. Here we demonstrate that the integrin VLA-4 is used in secondary adhesion after CD44-mediated primary adhesion of human and mouse T cells in vitro, and by mouse T cells in an in vivo model. We show that clonal cell lines and polyclonally activated normal T cells roll under physiologic shear forces on hyaluronate and require VCAM-1, but not ICAM-1, as ligand for subsequent firm adhesion. This firm adhesion is also VLA-4 dependent, as shown by antibody inhibition. Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site. Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4–mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes.

Authors

Mark H. Siegelman, Diana Stanescu, Pila Estess

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Figure 3

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Primary and secondary adhesion of SAKR cells on SVEC4-10 endothelial cel...
Primary and secondary adhesion of SAKR cells on SVEC4-10 endothelial cells under physiologic shear stress. SAKR cells were applied to feed solution already equilibrated under flow at a wall shear stress of 2.0 dynes/cm2 and the solution was perfused over the monolayer in the parallel plate flow assay. Rolling and sticking were analyzed as described, and the number of cells/field per minute rolling and number of bound cells/field were determined. For blocking, anti-CD44, anti–VLA-4, or anti-CD44 together with anti–VLA-4 was added to the cell suspension before introduction into the flow system. Rolling and firm adhesion were both blocked by anti-CD44, whereas only anti–VLA-4 was able to block firm adhesion. Data shown are from a representative of 3 experiments.