• Ingrid E Dumitriu, Paramita Baruah, Caroline J Finlayson, Ian M Loftus, Ricardo F Antunes, Pitt Lim, Nicholas Bunce, and Juan Carlos Kaski.
• Cardiovascular Sciences Research Centre, Division of Clinical Sciences, St. George's University of London, UK. i.dumitriu@sgul.ac.uk
• Circ. Res. 2012 Mar 16; 110 (6): 857-69.

RationalePatients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4(+)CD28(null) T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4(+)CD28(null) T cell function are unknown.ObjectiveOur aim was to investigate the expression and role of alternative costimulatory receptors in CD4(+)CD28(null) T cells in ACS.Methods And ResultsExpression of alternative costimulatory receptors (inducible costimulator, OX40, 4-1BB, cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4(+)CD28(null) T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4(+)CD28(null) T cells compared to classical CD4(+)CD28(+) T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4(+)CD28(null) T cells constituted an important proportion of CD4(+) T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4(+)CD28(null) T cells to produce interferon-γ and tumor necrosis factor-α and release perforin.ConclusionsCostimulatory pathways are altered in CD4(+)CD28(null) T cells in ACS. We show that the inflammatory and cytotoxic function of CD4(+)CD28(null) T cells can be inhibited by blocking OX40 and 4-1BB costimulatory receptors. Modulation of costimulatory receptors may allow specific targeting of this cell subset and may improve the survival of ACS patients.

37 keywords...

hide…