Different integrins mediate haptotaxis of T lymphocytes towards either lower or higher adhesion zones

Abstract

Guidance of cells by molecules anchored on a substrate, known as haptotaxis, is arguably crucial in development, immunology and cancer, however the exact cues and mechanisms driving cell orientation in vivo are hardly identified. Adhesive haptotaxis has been described in the case of mesenchymatous cells that develop strong pulling forces with their substrates and orient via a tug of war mechanism -a competition between cells' pulling edges. In the case of amoeboid cells that migrate with minimal interaction with their substrate, existence of adhesive haptotaxis remains unclear. Here, we studied the crawling of human T lymphocytes on substrates with spatially modulated adhesivity, and observed haptotaxis with surface concentrations of integrin ligands found on high endothelial veinules. Overexpression of ICAM-1 and VCAM-1 molecules observed in vivo at transmigration portals can therefore promote leukocyte recruitment. Mechanistically, we show that integrin-mediated haptotaxis of lymphocytes differ both from active chemotaxis, because no mechanotransduction was detected, and from the passive tug of war mechanism of mesenchymatous cells, because different integrins support opposite phenotypes. Cells favored more adherent zones with VLA-4 and, counterintuitively, less adherent zones with LFA-1. These results reveal that integrins control differential adhesive haptotaxis behaviors without mechanotransduction, and this smart capability may support unsuspected ways for cells path selection.

Generation of cell-derived matrices that support human NK cell migration and differentiation

“…20,21,27 They provide a useful model that mimics both the complex composition and substrate stiffness 28 The increased cell spreading that we observed following short-term 20,30,31 This likely reflects differences in the composition or structure of the matrices between stromal cell-derived matrices and fibroblast-derived matrices, as well as different requirements for haptotaxis between immune cells and those that undergo non-amoeboid cell migration. 32 Whereas migration did not require the presence of intact cells, direct contact between NK cell developmental precursors and stroma greatly increased the expansion of precursors in our system as previously reported. 15 The nature of the survival or proliferation signaling provided by stroma remains unknown, however previous studies have implicated conserved pathways such as Wnt and Notch, or secreted factors such as cytokines, in providing these signals.…”

“…Specifically, we did not detect haptotaxis induced by matrix topology, as has been reported for cells migrating on fibroblast‐derived ECM 20,30,31 . This likely reflects differences in the composition or structure of the matrices between stromal cell‐derived matrices and fibroblast‐derived matrices, as well as different requirements for haptotaxis between immune cells and those that undergo non‐amoeboid cell migration 32 . Taken together with the adhesion data described above, however, the conserved patterns of migration seen on CDMs and intact cells suggests that the migration of NK cell developmental intermediates in an in vitro differentiation system can occur independently of cell‐associated ligands, including ICAM and VCAM.…”

Amoeboid Swimming Is Propelled by Molecular Paddling in Lymphocytes

“…Interference microscopy attested that cells travelled across the adhesive zones with adhesive contact to the substrate (green signal) and across anti-adhesive zones with a lubrication film separating the cells from the substrate (no green signal). Cells were even found to have the same probability of presence on adherent and antiadherent stripe 38 . These observations suggest that the transition between adherent and non-adherent motility modes is fast, or that the two phenotypes share the same machinery, which altogether cancels the idea of switch between two modes.…”

“…Mat Movie 17 and Movie 18). Between plates, two adjacent zones with adherent and non-adherent coatings were prepared by optical patterning 38 and tube surfaces were treated with Pluronic F107 14 . Cells are slightly faster between plates and significantly faster in tubes as compared to swimming mode.…”

Generation of cell-free matrices that support human NK cell migration and differentiation

“…Specifically, we did not detect haptotaxis induced by matrix topology, as has been reported for cells migrating on fibroblast-derived ECM (20,31,32). This likely reflects differences in the composition or structure of the matrices between stromal cell-derived matrices and fibroblastderived matrices, as well as different requirements for haptotaxis between immune cells and those that undergo nonamoeboid cell migration (33). Taken together with the adhesion data described above, however, the conserved patterns of migration seen on CDMs and intact cells suggests that the migration of NK cell developmental intermediates in an in vitro differentiation system can occur independently of cellassociated ligands, including ICAM and VCAM.…”