MULTISTEP NAVIGATION AND THE COMBINATORIAL CONTROL OF LEUKOCYTE CHEMOTAXIS

Cells migrating within tissues may encounter multiple chemoattractant signals in complex spatial and temporal patterns. To understand leukoc yte navigation in such settings, we have explored the migratory behavi or of neutrophils in model scenarios where they are presented with two chemoattractant. sources in various configurations. We show that, ove r a wide range of conditions, neutrophils can migrate ''down'' a local chemoattractant gradient in response to a distant gradient of a diffe rent chemoattractant. Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant. Tog ether, these observations suggest the potential for cells' step-by-ste p navigation from one gradient to another in complex chemoattractant f ields. The importance of such sequential navigation is confirmed here in a model system in which neutrophil homing to a defined domain (a) r equires serial responses to agonists presented in a defined spatial ar ray, and (b) is a function of both the agonist combination and the seq uence in which gradients are encountered. We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localiz ation.