Reactive Oxidative Species-Modulated Ca2+ Release Regulates β2 Integrin Activation on CD4+ CD28null T Cells of Acute Coronary Syndrome Patients

The number and activity of T cell subsets in the atherosclerotic plaques are critical for the prognosis of patients with acute coronary syndrome. beta 2 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-1 alpha-mediated beta(2) 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 beta(2) integrin activation upon SDF-1 alpha 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 beta(2) 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.