'Reverse gear' cellular movement mediated by chemokines

We sought to model the mechanism by which leucocytes may be actively repuls ed by a beta -chemokine signal. This model is used to interpret an apparent paradox in chemokine biology, whereby high levels of a T-cell chemoattract ant, stromal cell derived factor-1 (SDF-1), are present in bone marrow and thymic tissues despite a paucity of mature T lymphocytes in these areas. We postulate the differential involvement in cell migration of the two bindin g sites on SDF-1 for its sole receptor, CXCR4, depending on whether high or low concentrations of SDF-1 are encountered by the cell. Site choice would be mediated by divergent affinities of the two binding interactions. We al so propose differential signalling following SDF-1/CXCR4 interactions on th e plasma membrane versus ligand/receptor complexes in endocytic vesicles. P reliminary data showing divergent susceptibility to kinase inhibitors depen ding on whether a cell is attracted to or repulsed by SDF-1, are consistent with this model. In terms of physical movement toward or away from a chemo kine gradient, we compare the cycling of surface receptors during migration to the caterpillar drive of a tractor, which can change direction simply b y altering the direction of rotation of its threads. Finally, the potential clinical implications of concentration-dependent, chemokine-based cell att raction and repulsion are discussed.