title: High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Cardiovascular Sciences Research Centre, Division of Clinical Sciences, St. George's University of London, UK. i.dumitriu@sgul.ac.uk
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
authors.forename: Paramita
authors.initials: P
authors.lastname: Baruah
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Finlayson
authors.forename: Ian M
authors.initials: IM
authors.lastname: Loftus
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Antunes
authors.forename: Pitt
authors.initials: P
authors.lastname: Lim
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bunce
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Kaski
mesh_terms: D054058:Acute Coronary Syndrome / Q000276:immunology* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D003324:Coronary Artery Disease / Q000276:immunology / Q000378:metabolism; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000378:metabolism; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D008024:Ligands; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes