Key Points Th1 cells rolling on selectins trigger DAP12-dependent activation of integrin αLβ2. DAP12 signaling in Th1 cells facilitates slow rolling, arrest, and migration. Visual Abstract During inflammation, both neutrophils and effector T cells use selectins to roll and integrins to arrest in postcapillary venules. In both cell types, chemokines can transduce signals that convert integrin αLβ2 to a high-affinity conformation, which interacts with ICAM-1 to mediate arrest. In neutrophils, selectins also trigger an immunoreceptor-like signaling cascade that converts integrin αLβ2 to an intermediate-affinity conformation, which interacts with ICAM-1 to slow rolling. It is not known whether selectins induce similar signaling events in T cells. Ag engagement causes phosphorylation of ITAMs on the TCR; these motifs recruit kinases and adaptors that lead to the activation of αLβ2. We found that mouse Th1 cells rolling on P- or E-selectin triggered signals that promoted αLβ2-dependent slow rolling on ICAM-1 in vitro and in vivo. The selectin signaling cascade resembled that used by the TCR, except that unexpectedly, Th1 cells employed the ITAM-bearing protein DAP12, which was not known to be expressed in these cells. Importantly, outside-in signaling through ligand-occupied αLβ2 also required DAP12. Cooperative selectin and chemokine signaling in Th1 cells promoted αLβ2-dependent slow rolling and arrest in vitro and in vivo and migration into Ag-challenged tissues in vivo. Our findings reveal an important function for DAP12 in Th1 cells and a new mechanism to recruit effector T cells to sites of inflammation.

中文翻译：

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Th1 细胞在选择素上滚动触发 DAP12 依赖性信号，激活整合素 αLβ2


要点 Th1 细胞在选择素上滚动会触发整合素 αLβ2 的 DAP12 依赖性激活。 Th1 细胞中的 DAP12 信号传导有助于缓慢滚动、停滞和迁移。视觉摘要 在炎症过程中，中性粒细胞和效应 T 细胞都使用选择素进行滚动，并使用整合素在毛细血管后微静脉中停滞。在这两种细胞类型中，趋化因子可以转导信号，将整合素 αLβ2 转化为高亲和力构象，与 ICAM-1 相互作用以介导阻滞。在中性粒细胞中，选择素还会触发类似免疫受体的信号级联反应，将整合素 αLβ2 转化为中间亲和力构象，与 ICAM-1 相互作用以减慢滚动速度。目前尚不清楚选择素是否会在 T 细胞中诱导类似的信号传导事件。 Ag 参与导致 TCR 上 ITAM 磷酸化；这些基序招募激酶和接头，导致 αLβ2 的激活。我们发现小鼠 Th1 细胞在 P-或 E-选择素上滚动会触发信号，在体外和体内促进 ICAM-1 上 αLβ2 依赖性的缓慢滚动。选择素信号级联与 TCR 使用的类似，但出乎意料的是，Th1 细胞使用了携带 ITAM 的蛋白 DAP12，而目前尚不清楚该蛋白是否在这些细胞中表达。重要的是，通过配体占据的 αLβ2 的由外向内信号传导也需要 DAP12。 Th1 细胞中选择素和趋化因子信号传导的协同作用在体外和体内促进了 αLβ2 依赖性缓慢滚动和停滞，并迁移到体内 Ag 攻击的组织中。我们的研究结果揭示了 DAP12 在 Th1 细胞中的重要功能以及将效应 T 细胞募集到炎症部位的新机制。