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 Ca 2+ influx induces T cell membrane-proximal external Ca 2+ concentration ([Ca 2+ ] ex ) drop in 6?s from physiological concentration 1.2?mM to 0.3?mM, a critical extracellular Ca 2+ 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 [Ca 2+ ] ex drop-triggered αLβ2 quick activation. Blocking Ca 2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca 2+ ] 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.
Ca2+ transients on the T cell surface trigger rapid integrin activation in a timescale of seconds
- 期刊：Nature Communications
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