Recruitment of leukocytes from blood vessels to inflamed zones is guided by biochemical and mechanical stimuli, with the mechanisms only partially deciphered. Here, we studied the guidance by the flow of primary human effector T lymphocytes crawling on substrates coated with ligands of integrins lymphocyte function-associated antigen 1 (LFA-1) (αLβ2) and very late antigen 4 (VLA-4) (α4β1). 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 integrin affinities, combined with an inhibiting cross talk of LFA-1 toward VLA-4. At the cellular level, direction is determined by the passive, flow-mediated orientation of the nonadherent 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.

中文翻译：

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由整合素介导的双稳态机制控制白细胞趋向性

白细胞从血管募集到发炎区域是由生化和机械刺激引导的，其机制仅部分被破译。在这里，我们研究了原代人类效应 T 淋巴细胞在涂有整合素淋巴细胞功能相关抗原 1 (LFA-1) (αLβ2) 和极晚期抗原 4 (VLA-4) (α4β1) 配体的基质上爬行的指导. 我们揭示了细胞在两个相反方向的群体中分离以进行组合粘附，并表明方向的决定依赖于 LFA-1 介导的上游和 VLA-4 介导的下游表型之间的双稳态机制。在分子水平上，双稳态是由两种整联蛋白亲和力的前后极化差异导致的，再加上 LFA-1 对 VLA-4 的抑制串扰。在细胞层面，方向由非粘附细胞部分的被动、流动介导的方向决定，后足类动物用于上游迁移，前片状足类动物用于下游迁移。这个逻辑事件链提供了一个综合的指导机制，从刺激到细胞定向。