Chemokine-triggered cell adhesion and integrin-mediated migration are crucial steps in the control of efficient immune-cell trafficking, yet the signalling molecules involved in these processes have been poorly defined. Now, Katagiri and colleagues report in Nature Immunology that the effector molecule RAPL (regulator of cell adhesion and polarization enriched in lymphoid tissues) has a vital role in immune-cell trafficking.

Recently, these researchers identified RAPL as an effector molecule for the GTPase RAP1, which is known to activate integrins, such as lymphocyte function-associated antigen 1 (LFA1) and very late antigen 4 (VLA4), and invoke cell polarization and motility. So, to investigate whether RAPL is important in immune-cell trafficking in vivo, they generated RAPL-deficient mice. T and B cells isolated from these mice had reduced ability to adhere to ICAM1 or VCAM1 (the ligands for LFA1 and VLA4, respectively) when exposed to chemokines, even though expression levels of the integrins or chemokine receptors were indistinguishable from those of wild-type cells. In addition, in the presence of chemokines, the RAPL-deficient lymphocytes had impaired adhesion and transmigration through endothelial-cell monolayers. In wild-type cells, chemokine-stimulated LFA1 activation by RAP1 is accompanied by lymphocyte polarization; however, the authors did not see a redistribution of LFA1 in the RAPL-deficient cells following chemokine stimulation, indicating a crucial role for RAPL in integrin activation.

Owing to these functional defects in lymphocyte adhesion and migration, RAPL-deficient mice had reduced T- and B-cell numbers in the spleen and lymph-node follicles, indicating impaired homing to peripheral lymphoid organs. Similarly, in the absence of RAPL, CD11c+ splenic dendritic cells (DCs) and epidermal Langerhans cells showed markedly reduced migration to the white pulp of the spleen or draining lymph nodes after exposure to an inflammatory stimulus.

In addition to the key role of RAPL in cell trafficking to lymphoid organs, the authors showed that it was also required for movement within and out of lymphoid organs. Accordingly, mature T cells accumulated in the thymi of RAPL-deficient mice because of defective emigration of thymocytes. Also, the maturation of B cells in RAPL-deficient spleens was impaired, resulting in reduced numbers of mature B cells in the marginal zones and blood, consistent with a requirement for integrin-mediated compartmentalization during splenic B-cell maturation.

Together, these results confirm that RAPL is a key regulator of cell 'stickiness' through integrin activation and is thereby crucial for effective immune-cell adhesion and migration.