title: 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-gamma 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-gamma 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.
authors.affiliation: Division of Cardiac and Vascular Sciences, St. George's University of London, London, United Kingdom. bzal@sgul.ac.uk
authors.forename: Behnam
authors.initials: B
authors.lastname: Zal
authors.forename: Juan C
authors.initials: JC
authors.lastname: Kaski
authors.forename: Julius P
authors.initials: JP
authors.lastname: Akiyu
authors.forename: Della
authors.initials: D
authors.lastname: Cole
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.forename: Jan
authors.initials: J
authors.lastname: Poloniecki
authors.forename: Alejandro
authors.initials: A
authors.lastname: Madrigal
authors.forename: Anthony
authors.initials: A
authors.lastname: Dodi
authors.forename: Christina
authors.initials: C
authors.lastname: Baboonian
mesh_terms: D054058:Acute Coronary Syndrome / Q000276:immunology; D000368:Aged; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018834:Chaperonin 60 / Q000276:immunology; D003324:Coronary Artery Disease / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000276:immunology; D054353:Perforin / Q000276:immunology*; D054340:Receptors, KIR / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D018834:Chaperonin 60; D015395:Histocompatibility Antigens Class I; C433932:KIR2DS2 protein, human; D010455:Peptides; D054340:Receptors, KIR; D054353:Perforin; D007371:Interferon-gamma