Nature Communications ( IF 14.7 ) Pub Date : 2024-07-20 , DOI: 10.1038/s41467-024-50464-0 Yue Li , ShiHui Wang , YouHua Zhang , ZhaoYuan Liu , YunZhe Zheng , Kun Zhang , ShiYang Chen , XiaoYing Lv , MengWen Huang , XingChao Pan , YaJuan Zheng , MengYa Yuan , GaoXiang Ge , Yi Arial Zeng , ChangDong Lin , JianFeng Chen
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One question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLβ2 activation, triggering rapid αLβ2 activation and T cell arrest before occurrence of αLβ2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLβ2 but not [Ca2+]ex drop-triggered αLβ2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location.
中文翻译:
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T 细胞表面的 Ca2+ 瞬变在数秒内触发整合素快速激活
淋巴细胞归巢的一个问题是,在趋化因子诱导的整合素由内向外缓慢激活的情况下,整合素如何快速激活,以便在目标血管床遇到趋化因子时立即阻止快速滚动的淋巴细胞。在此,我们证明趋化因子 CCL25 触发的 Ca 2+ 流入诱导 T 细胞膜近端外部 Ca 2+ 浓度([Ca 2+ ] ex ) 在 6 秒内从生理浓度 1.2 mM 降至 0.3 mM,这是诱导 αLβ2 激活的关键细胞外 Ca 2+ 阈值,在发生 αLβ2 由内而外激活之前触发快速 αLβ2 激活和 T 细胞停滞。 Talin 敲低抑制 αLβ2 由内而外的缓慢激活,但不抑制 [Ca 2+ ] ex 滴触发的 αLβ2 快速激活。在小鼠银屑病模型中,阻断 Ca 2+ 流入可显着抑制 T 细胞从滚动到停滞的转变和归巢到皮肤病变,从而减轻皮肤炎症。 [Ca 2+ ] ex 减少触发的快速整合素激活弥合了初始趋化因子刺激和缓慢整合素由内而外激活之间的差距,确保淋巴细胞立即停滞并随后在正确位置发生渗出。