Leukocyte trafficking Sample Clauses

Leukocyte trafficking. DCs are known to be the most potent APCs of the immune system, and much of the work towards elucidating the mechanisms of lymphatic transmigration has therefore used DCs. In homeostasis, DCs continue to migrate from the periphery to the DLN in order to present self-antigens. This is crucial for the maintenance of tolerance to self, and indeed mice lacking lymphatic vessels develop severe autoimmunity due to a defect in the homeostatic transport of DCs (123). Under steady-state conditions, DCs move in an amoeboid fashion towards the lymphatic vessel in an integrin-independent process (124, 125), that requires a chemotactic chemokine gradient (126). The chemokine- receptor pair crucial for lymphatic migration of DCs is CCL21, which is produced by LECs, and CCR7, which is expressed by DCs. DCs then enter the lymphatic vessel at portals, which are areas between LEC adherens junctions where basement membrane is least dense (127). From here they move inside the vessel in the direction of lymph flow towards the collecting vessel and ultimately enter the DLN. Under inflammatory conditions, the extra-cellular matrix of the interstitium is not conducive to the amoeboid movement of DC due to loosening of the collagen fibres (128). Therefore, entry of DC into the lymphatic vessel lumen becomes an active process dependent on integrins, particularly intercellular adhesion molecule (ICAM) -1 (Figure 1.2). The seminal paper by Xxxxxxx et al. showed that DC transmigration across the lymphatic endothelium in inflammatory conditions was dependent on ICAM-1, and that this process could be blocked in vitro by administering anti-ICAM-1 antibodies (129). In inflammation, movement of DCs towards the vessel is still dependent on a CCL21 chemokine gradient, and in fact LECs increase secretion of CCL21 following an inflammatory stimulus (130). As interstitial flow increases toward the lymphatic vessel, more CCL21 is needed to maintain the gradient in favour of guiding DCs towards the vessel. CCL21 is also able to bind to heparan sulphates within the extra-cellular matrix in order to prevent it being washed away by the flow of fluid in the opposite direction (131). In addition, it has been found that migration of immune cells to DLN is unaffected when lymphatic vessels are sparse, even if flow is dramatically decreased, because the CCL21 gradient becomes more favourable (132). Again DCs then enter the lymphatic vessel lumen at portals where basement membrane is least dense. It is app...
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Related to Leukocyte trafficking

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