The affinity of integrin alpha(4)beta(1) governs lymphocyte migration

The interaction of integrin alpha (4)beta (1) with endothelial VCAM-1 contr ols the trafficking of lymphocytes from blood into peripheral tissues. Cell s actively regulate the affinity of alpha (4)beta (1) for VCAM-1 (activatio n). To investigate the biological function of alpha (4)beta (1) activation, we isolated Jurkat T cell lines with defective alpha (4)beta (1) activatio n. Using these cells, we found that alpha (4)beta (1)-stimulated alpha (L)b eta (2)-dependent cell migration was dramatically reduced in cells with def ects in alpha (4)beta (1) activation. These cells required 20 times more VC AM-1 to promote alpha (L)beta (2)-dependent cell migration. This defect was at the level of alpha (4)beta (1) affinity as an activating alpha (4)beta (1) Ab rescued alpha (4)beta (1)-stimulated alpha (L)beta (2)-dependent mig ration. In contrast, migration of alpha (4)beta (1) activation-defective ce lls on VCAM-1 alone was enhanced at higher VCAM-1 densities. Thus, alpha (4 )beta (1) activation determines a set point or threshold at which VCAM-1 ca n regulate alpha (L)beta (2)-dependent as well as alpha (4)beta (1)-depende nt cell migration. Changes in this set point may specify preferred anatomic al sites of integrin-dependent leukocyte emigration from the bloodstream.