Patients 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.

Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4⁺CD28^null T cells in ACS.

Expression 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.

Costimulatory 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.