Regulation of cell migration by stop signals

The accumulation of antigen specific T lymphocytes at sites of antigenic challenge is an important potential example of regulated leukocyte migration. A key engine for lymphocyte migration in tissues is based on engagement of integrin receptors and coordinated cytoskeletal responses that translate integrin engagement into cell movement. We hypothesized that antigen receptor engagement would regulate lymphocyte migration by changing the outcome of integrin engagement from migration to firm in situ adhesion. To test this hypothesis we have developed an in vitro system where we can simultaneously view cell migration, integrin engagement and antigen receptor engagement. We found that interaction of the integrin LFA1 with its ligand ICAM-I promotes fast, random migration of effector lymphocytes. Strikingly, antigen receptor engagement stops migration. Thus, antigen receptor engagement provides a dominant stop signal for lymphocyte migration that allows prolonged interaction with antigen presenting cells. The stop signal was accompanied by a change in the organization of the T cell cytoskeleton and an increase in LFA-1 engagement Time-lapse observations show that stopped T cell remain highly dynamic, but focus on a central site of antigen receptor engagement. In contrast, chemokines also signal increased integrin engagement, but in a manner that leads to greater locomotion, rather than a stop signal. Thus, signals that activate adhesion mechanisms can have distinct outcomes-stop or go-depending upon simultaneous effects on cytoskeletal organization. Simple loss or gain of adhesion receptors cannot fully explain migratory decision making.