Regulation of immune cell trafficking by adhesion molecules and immune responses

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Dynamic regulation of immune cell trafficking is central to immuno-surveillance. Motile lymphocyte is a fundamental component regulating this process. Our understanding of lymphocyte trafficking has been facilitated by identification of chemokines and adhesion molecules such as LFA-1 and a4 integrins, which play important roles in mediating transmigration through endothelium and antigen recognition. We have shown that small GTPase Rap1 regulates integrin-mediated adhesion and promotes lymphocyte adhesive responses and migration. In this study, we showed that a novel Rap1 effector RAPL positively regulated integrin-mediated adhesion triggered by chemokines and specific antigen, depending on Rapl. Rap1/RAPL signaling coordinately regulates integrin distribution and cell polarity, thereby generates lymphocyte robust migration. We further identified Mstl (STK4) belonging to the Ste20-related serine/threonine kinase family. Upon binding to Rap1-GTP, RAPL physically bound to Mstl through the … More coiled-coil domain of RAPL, and increased Mstl kinase activities. Activated Mstl mediated LFA-1 surface clustering induced by chemokine and TCR crosslinking. RAPL and Mstl were exclusively co-fractionated in light-density compartments enrich for vesicle components containing LFA-1 and Rap1 by sucrose-density centrifugation, suggesting RAPL and Mstl regulate intracellular vesicle transport of LFA-1. In order to investigate physiological roles of RAPL signaling in vivo, we generated RAPL-deficient mice. RAPL-deficient lymphocytes were defective in stable adhesion to the high endothelium, leading to inefficient entry into tissues, resulting hypocellularity of secondary lymph nodes. In addition, we found that dendritic antigen-presenting cells abundantly expressed RAPL. RAPL-deficient skin dendritic cells were impaired in migration to draining lymph nodes upon inflammation. Collectively, we demonstrate that RAPL signaling plays critical roles in in vivo trafficking of lymphocytes and dendritic cells essential for immunosurveillance through regulating integrin-mediated adhesive behaviors. Less