Reactive Oxidative Species–Modulated Ca²⁺ Release Regulates β₂ Integrin Activation on CD4⁺ CD28^null T Cells of Acute Coronary Syndrome Patients

Abstract

The number and activity of T cell subsets in the atherosclerotic plaques are critical for the prognosis of patients with acute coronary syndrome. β₂ Integrin activation is pivotal for T cell recruitment and correlates with future cardiac events. Despite this knowledge, differential regulation of adhesiveness in T cell subsets has not been explored yet. In this study, we show that in human T cells, SDF-1α–mediated β₂ integrin activation is driven by a, so far, not-described reactive oxidative species (ROS)–regulated calcium influx. Furthermore, we show that CD4⁺CD28^null T cells represent a highly reactive subset showing 25-fold stronger β₂ integrin activation upon SDF-1α stimulation compared with CD28⁺ T cells. Interestingly, ROS-dependent Ca release was much more prevalent in the pathogenetically pivotal CD28^null subset compared with the CD28⁺ T cells, whereas the established mediators of the classical pathways for β₂ integrin activation (PKC, PI3K, and PLC) were similarly activated in both T cell subsets. Thus, interference with the calcium flux attenuates spontaneous adhesion of CD28^null T cells from acute coronary syndrome patients, and calcium ionophores abolished the observed differences in the adhesion properties between CD28⁺ and CD28^null T cells. Likewise, the adhesion of these T cell subsets was indistinguishable in the presence of exogenous ROS/H₂O₂. Together, these data provide a molecular explanation of the role of ROS in pathogenesis of plaque destabilization.