A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes


  • Hornung Alexander
  • Sbarrato Thomas
  • Garcia-Seyda Nicolas
  • Aoun Laurene
  • Luo Xuan
  • Biarnes-Pelicot Martine
  • Theodoly Olivier
  • Valignat Marie-Pierre

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Recruitment of leukocytes from blood vessels to inflamed zones is guided by biochemical and mechanical stimuli, with mechanisms only partially deciphered. Here, we studied the guidance by flow of primary human effector T lymphocytes crawling on substrates coated with ligands of integrins LFA-1 (aLb2) and VLA-4 (a4b1). We reveal that cells segregate in two populations of opposite orientation for combined adhesion, and show that decisions of orientation rely on a bistable mechanism between LFA-1-mediated upstream and VLA-4-mediated downstream phenotypes. At the molecular level, bistability results from a differential front-rear polarization of both integrins affinity, combined with an inhibiting crosstalk of LFA-1 towards VLA-4. At the cellular level, direction is determined by the passive, flow-mediated orientation of the non-adherent cell parts, the rear uropod for upstream migration and the front lamellipod for downstream migration. This chain of logical events provides a comprehensive mechanism of guiding, from stimuli to cell orientation.

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