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

• DOI: 10.1161/circresaha.111.261933
• Publication Date: 2012-01-27T03:56:37Z
• Authors: Ingrid E. Dumitriu; Paramita Baruah; Caroline J. Finla...; Ian M. Loftus; Ricardo F. Antunes; Pitt Lim; Nicholas Bunce; Juan Carlos Kaski
• Keywords: Aged, 80 and over; CD4-Positive T-Lymphocytes; Male; Perforin; Coronary Artery Disease; Middle Aged; Receptors, OX40; Ligands; Cell Degranulation; Granzymes; CD4 Lymphocyte Count; 3. Good health; Tumor Necrosis Factor Receptor Superfamily, Member 9; 03 medical and health sciences; 0302 clinical medicine; CD28 Antigens; CD4 Antigens; Humans; Female; Acute Coronary Syndrome; Aged; Signal Transduction

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.