Differential Pathways Govern CD4+CD28− T Cell Proinflammatory and Effector Responses in Patients with Coronary Artery Disease
2008
Patients with acute coronary syndromes experience circulatory and intraplaque expansion of an aggressive and unusual CD4 + lymphocyte subpopulation lacking the CD28 receptor. These CD4 + CD28 − cells produce IFN-γ and perforin, and are thought to play an important role in coronary atheromatous plaque destabilization. Aberrant expression of killer Ig-like receptors (KIRs) in CD4 + CD28 − cells is broadly thought to be responsible for their cytotoxicity, but the mechanisms involved remain poorly defined. We therefore sought to investigate the mechanism and regulation of CD4 + CD28 − cell functionality using T cell clones ( n = 536) established from patients with coronary artery disease ( n = 12) and healthy volunteers ( n = 3). Our functional studies demonstrated that KIR2DS2 specifically interacted with MHC class I-presenting human heat shock protein 60 (hHSP60) inducing cytotoxicity. Further investigations revealed the novel finding that hHSP60 stimulation of TCR alone could not induce a cytotoxic response, and that this response was specific and KIR dependent. Analysis of CD4 + CD28 − 2DS2 + clones ( n = 162) showed that not all were hHSP60 cytotoxic; albeit, their prevalence correlated with coronary disease status ( p = 0.017). A higher proportion of clones responded to hHSP60 by IFN-γ compared with perforin ( p = 0.008). In this study, for the first time, we define the differential regulatory pathways involved in CD4 + CD28 − cell proinflammatory and effector responses. We describe in this study that, contrary to previous reports, CD4 + CD28 − cell recognition and killing can be specific and discriminate. These results, in addition to contributing to the understanding of CD4 + CD28 − cell functionality, may have implications for the monitoring and management of coronary artery disease progression.
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