High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome

Ingrid Dumitriu, Paramita Baruah, Caroline J Finlayson, Ian M Loftus, Ricardo F Antunes, Pitt Lim, Nicholas Bunce, Juan Carlos Kaski

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)857-69
Number of pages13
JournalCirculation Research
Issue number6
Publication statusPublished - 16 Mar 2012


  • Acute Coronary Syndrome/immunology
  • Aged
  • Aged, 80 and over
  • CD28 Antigens/genetics
  • CD4 Antigens/genetics
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes/cytology
  • Cell Degranulation/immunology
  • Coronary Artery Disease/immunology
  • Female
  • Granzymes/metabolism
  • Humans
  • Ligands
  • Male
  • Middle Aged
  • Perforin/metabolism
  • Receptors, OX40/immunology
  • Signal Transduction/immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology


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