High Levels of Costimulatory Receptors OX40 and 4-1BB Characterize CD4 + CD28 null T Cells in Patients With Acute Coronary Syndrome

Abstract

Rationale: 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. Objective: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4 + CD28 null T cells in ACS. Methods and Results: 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. Conclusions: 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.