ICAMS REDISTRIBUTED BY CHEMOKINES TO CELLULAR UROPODS AS A MECHANISM FOR RECRUITMENT OF T-LYMPHOCYTES

The recruitment of leukocytes from the bloodstream is a key step in th e inflammatory reaction, and chemokines are among the main regulators of this process. During lymphocyte-endothelial interaction, chemokines induce the polarization of T lymphocytes, with the formation of a cyt oplasmic projection (uropod) and redistribution of several adhesion mo lecules (ICAM-1,-3, CD43, CD44) to this structure. Although it has bee n reported that these cytokines regulate the adhesive state of integri ns in leukocytes, their precise mechanisms of chemoattraction remain t o be elucidated. We have herein studied the functional role of the lym phocyte uropod. Confocal microscopy studies clearly showed that cell u ropods project away from the cell bodies of adhered lymphocytes and th at polarized T cells contact other T cells through the uropod structur e, Time-lapse videomicroscopy studies revealed that uropod-bearing T c ells were able, through this cellular projection, to contact, capture, and transport additional bystander T cells. Quantitative analysis rev ealed that the induction of uropods results in a 5-10-fold increase in cell recruitment. Uropod-mediated cell recruitment seems to have phys iological relevance, since it was promoted by both CD45R0(+) periphera l blood memory T cells as well as by in vivo activated lymphocytes. Ad ditional studies showed that the cell recruitment mediated by uropods was abrogated with antibodies to ICAM-1, -3, and LFA-1, whereas mAb to CD43, CD44, CD45, and L-selectin did not have a significant effect, t hus indicating that the interaction of LFA-1 with ICAM-1 and -3 appear s to be responsible for this process. To determine whether the increme nt in cell recruitment mediated by uropod may affect the transendothel ial migration of T cells, we carried out chemotaxis assays through con fluent monolayers of endothelial cells specialized in lymphocyte extra vasation. An enhancement of T cell migration was observed under condit ions of uropod formation, and this increase was prevented by incubatio n with either blocking anti-ICAM-3 mAbs or drugs that impair uropod fo rmation. These data indicate that the cell interactions mediated by ce ll uropods represent a cooperative mechanism in lymphocyte recruitment , which may act as an amplification system in the inflammatory respons e.