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Chemokines regulate rapid leukocyte adhesion by triggering a complex modality of integrin activation. We show that the small GTPase RhoA and the atypical ζ PKC differently control lymphocyte LFA-1 high-affinity state and rapid lateral mobility induced by chemokines. Activation of LFA-1 high-affinity state and lateral mobility is controlled by RhoA through the activity of distinct effector regions, demonstrating that RhoA is a central point of diversification of signaling pathways leading to both modalities of LFA-1 triggering. In contrast, ζ PKC controls LFA-1 lateral mobility but not affinity triggering. Blockade of the 23–40 RhoA effector region prevents induction of LFA-1 high-affinity state as well as lymphocyte arrest in Peyer's patch high endothelial venules. Thus, RhoA controls the induction of LFA-1 high-affinity state by chemokines independently of ζ PKC, and this is critical to support chemokine-regulated homing of circulating lymphocytes.

Chemokines trigger rapid integrin-dependent lymphocyte arrest to vascular endothelium. We show that the chemokines SLC, ELC, and SDF-1α rapidly induce lateral mobility and transient increase of affinity of the β2 integrin LFA-1. Inhibition of phosphatidylinositol 3-OH kinase (PI(3)K) activity blocks mobility but not affinity changes and prevents lymphocyte adhesion to ICAM-1 immobilized at low but not high densities, suggesting that mobility enhances the frequency of encounters between high-affinity integrin and ligand but that at higher ligand density affinity changes are sufficient for arrest. Thus, chemokines trigger, through distinct signaling pathways, both a high-affinity state and lateral mobility of LFA-1 that can coordinately determine the vascular arrest of circulating lymphocytes under physiologic conditions.