Key Points
CD28null T cells show high reactivity of β2 integrin upon chemokine stimulation.
ROS-mediated Ca2+ release is critical for β2 integrin activation in T cells.
Spontaneous β2 integrin activity of CD28null T cells in ACS is ROS dependent.
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.
Footnotes
The online version of this article contains supplemental material.
Abbreviations used in this article:
- ACS
- acute coronary syndrome
- Apo
- apocynin
- DPI
- diphenylene iodonium chloride
- LC-AA
- ligand complex–based adhesion assay
- MFI
- mean fluorescence intensity
- NAC
- N-acetylcysteine
- Ptx
- pertussis toxin
- redox
- oxidation reduction
- RFP
- red fluorescence protein
- roGFP
- redox-sensitive GFP
- ROS
- reactive oxidative species.
- Received March 28, 2020.
- Accepted August 17, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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