T Lymphocytes Orient against the Direction of Fluid Flow during LFA-1-Mediated Migration

Abstract

As they leave the blood stream and travel to lymph nodes or sites of inflammation, T lymphocytes are captured by the endothelium and migrate along the vascular wall to permissive sites of transmigration. These processes take place under the influence of hemodynamic shear stress; therefore, we investigated how migrational speed and directionality are influenced by variations in shear stress. We examined human effector T lymphocytes on intercellular adhesion molecule 1 (ICAM-1)-coated surfaces under the influence of shear stresses from 2 to 60 dyn.cm(-2). T lymphocytes were shown to respond to shear stress application by a rapid (30 s) and fully reversible orientation of their migration against the fluid flow without a change in migration speed. Primary T lymphocytes migrating on ICAM-1 in the presence of uniformly applied SDF-1α were also found to migrate against the direction of shear flow. In sharp contrast, neutrophils migrating in the presence of uniformly applied fMLP and leukemic HSB2 T lymphocytes migrating on ICAM-1 alone oriented their migration downstream, with the direction of fluid flow. Our findings suggest that, in addition to biochemical cues, shear stress is a contributing factor to leukocyte migration directionality.

Lymphocytes can self-steer passively with wind vane uropods

“…The total shear force on the cells (B100 pN at 10 dyn cm À 2 ) is known to be negligible as compared with the force developed by the powerful motility machinery in the lamellipod (41,000 pN; ref. 4). This has previously permitted us to explain why cell velocity remains unaffected by flow 4 , but it also supports the idea that migration orientation is a specific adaptation of lymphocytes to the relatively faint hydrodynamic cue.…”

“…4). This has previously permitted us to explain why cell velocity remains unaffected by flow 4 , but it also supports the idea that migration orientation is a specific adaptation of lymphocytes to the relatively faint hydrodynamic cue. However, it is unknown whether this adaptation is active or passive, or whether it arises Schematic mechanistic pictures for chemotaxis and flow mechanotaxis of the spatial variation of (grey) the external stimuli, (green) the molecular sensor distribution and (orange) the cell internal signalling by molecular sensors.…”

“…In fact, cell multiplets form quasi-stable patterns with an immobile 'crosslinking' point at the centre and cells pulling radially in diverging directions with regular angles between cells. The independence of orientation with flow is consistent with the fact that mutual tractions between cells induced by their powerful motility machinery overcome the hydrodynamic shear stress on each cell 4 . Moreover, according to Newton's law, the sum of forces on the immobile bead of a multiplet is null at equilibrium, and considering that each cell roughly develops the same force and pulls away from its uropod, multiplets of n cells are expected to form regular star patterns with angles between branches of 2p/n.…”

“…Before extravasation from the blood stream into tissues, circulating leukocytes arrest and crawl with an amoeboid motility 1 on the luminal surface of blood vessels under the influence of an intense shear stress exerted by flowing blood. The role of flow on leukocyte crawling and extravasation remains generally an unsolved question 2 ; however, crawling T lymphocytes were recently reported in vivo 3 and in vitro 4 to orient against the direction of flow and to move upstream similar to salmon in a river. This non-intuitive behaviour is manifestly not a drift of cells pushed by the flow, and we sought here to clarify the origin, role and mechanism of this upstream flow mechanotactic behaviour.…”

Chemical and mechanical stimuli act on common signal transduction and cytoskeletal networks

“…Similarly to Dictyostelium, neutrophils and T lymphocytes have also been previously reported to directionally migrate in response to shear flow (30,31). However, whether the acute response that was observed in human neutrophils in this study is a prerequisite for shear flow-induced migration as it is in Dictyostelium remains to be examined.…”