Ca²⁺ transients on the T cell surface trigger rapid integrin activation in a timescale of seconds

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.