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

J Immunol. 2020 Oct 15;205(8):2276-2286. doi: 10.4049/jimmunol.2000327. Epub 2020 Sep 16.

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+CD28null 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 CD28null 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 CD28null T cells from acute coronary syndrome patients, and calcium ionophores abolished the observed differences in the adhesion properties between CD28+ and CD28null 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.

MeSH terms

  • Acute Coronary Syndrome / immunology*
  • Acute Coronary Syndrome / pathology
  • CD18 Antigens / immunology*
  • CD28 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Calcium Signaling / immunology*
  • Chemokine CXCL12 / immunology
  • Female
  • Humans
  • Male
  • Reactive Oxygen Species / immunology*

Substances

  • CD18 Antigens
  • CD28 Antigens
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Reactive Oxygen Species