title: Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4.
abstract: Dendritic cells (DCs) respond to chemotactic signals to migrate from sites of infection to secondary lymphoid organs where they initiate the adaptive immune response. The key chemokines directing their migration are CCL19, CCL21, and CXCL12, but how signals from these chemokines are integrated by migrating cells is poorly understood. Using a microfluidic device, we presented single and competing chemokine gradients to murine bone-marrow derived DCs in a controlled, time-invariant microenvironment. Experiments performed with counter-gradients revealed that CCL19 is 10-100-fold more potent than CCL21 or CXCL12. Interestingly, when the chemoattractive potencies of opposing gradients are matched, cells home to a central region in which the signals from multiple chemokines are balanced; in this region, cells are motile but display no net displacement. Actin and myosin inhibitors affected the speed of crawling but not directed motion, whereas pertussis toxin inhibited directed motion but not speed. These results provide fundamental insight into the processes that DCs use to migrate toward and position themselves within secondary lymphoid organs.
authors.affiliation: Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brendon G
authors.initials: BG
authors.lastname: Ricart
authors.forename: Beena
authors.initials: B
authors.lastname: John
authors.forename: Dooyoung
authors.initials: D
authors.lastname: Lee
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hammer
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000502:physiology; D054377:Chemokine CXCL12 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques / Q000379:methods; D009218:Myosins / Q000037:antagonists & inhibitors / Q000502:physiology; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000199:Actins; C514936:CXCR4 protein, mouse; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D009218:Myosins