Differential Pathways Govern CD4+CD28− T Cell Proinflammatory and Effector Responses in Patients with Coronary Artery Disease

Abstract

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.

Pathogenic features of CD4+CD28– T cells in immune disorders

“…Furthermore, TCR stimulation with hHSP60 was not sufficient to induce cytotoxicity. Instead, the interaction of KIR2DS2, an activating NK cell receptor, with major histocompatibility complex (MHC) class I presenting hHSP60 induced a specific cytotoxic response [57]. These findings suggest that killing by CD4 + CD28 -T cells is not TCR-dependent, but can be antigen specific.…”

CD28 Negative T Cells: Is Their Loss Our Gain?

“…Mechanistically, the KIRs expressed on CD4 + CD28 − T cells have been implicated in contributing to this proinflammatory phenotype. 25,26 Interestingly, patients with end-stage renal disease suffer remarkably high risk for acute atherosclerotic vascular events shortly after kidney transplantation. 27 Traditional risk factors such as smoking, hypertension, and hypercholesterolemia insufficiently account for the magnitude of this risk.…”

Molecular Mechanisms Involved in the Aging of the T-cell Immune Response

“…( 5 ). In the case of artery disease and CMV infection, the expression of KIR receptors in CD4+CD28 null T cells is broadly accepted to be responsible for their functionality [138, 139]. Meanwhile, progression of the rheumatic diseases is thought to be accompanied by the recruitment and rise of oligoclonal, autoreactive CD4+CD28null T cells, present a low activation threshold in response to TCR stimulation, which could be implicated in its predisposition to the breakdown of self-tolerance [140].…”