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

Behnam Zal^1,*, Juan C. Kaski^*, Julius P. Akiyu^*, Della Cole^*, Gavin Arno^*, Jan Poloniecki, Alejandro Madrigal, Anthony Dodi and Christina Baboonian^*

^* Division of Cardiac and Vascular Sciences, St. George’s University of London, London, United Kingdom; Department of Community Health Sciences, St. George’s University of London, London, United Kingdom; Anthony Nolan Research Institute, Royal Free & University College London, London, United Kingdom; and School of Biomedical and Natural Sciences, Nottingham Trent University, Nottingham, United Kingdom

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- 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Behnam Zal, Division of Cardiac and Vascular Sciences, St. George’s University of London, Cranmer Terrace, London, SW17 0RE, U.K. E-mail address: bzal{at}sgul.ac.uk

² Abbreviations used in this paper: ACS, acute coronary syndrome; CAD, coronary artery disease; CSA, chronic stable angina; HCMV, human CMV; hHSP, human heat shock protein; HSP, heat shock protein; KIR, killer Ig-like receptor; LDH, lactate dehydrogenase; mpc, mean percentage cytotoxicity; NSTE, non-ST elevation; RV, rheumatoid vasculitis; UA, unstable angina.