Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome

E Kovalcsik, Ricardo F. Antunes, Paramita BARUAH, JC Kaski, Ingrid Dumitriu

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


Background: The number of CD4+CD28null (CD28null) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28null T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28null T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28null T cells in ACS.

Methods and Results: We found that CD28null T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was attributable to a dramatic reduction in proapoptotic molecules Bim, Bax, and Fas in CD28null T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28null and CD28+ T cells. We also show that Bim is phosphorylated in CD28null T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28null T cells in ACS.

Conclusions: We show that CD28null T cells in ACS harbor marked defects in molecules that regulate T-cell apoptosis, which tips the balance in favor of antiapoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that the inhibition of proteasomal activity allows CD28null T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control the apoptosis sensitivity of CD28null T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients.
Original languageEnglish
Pages (from-to)709-720
Number of pages12
Issue number8
Early online date19 Dec 2014
Publication statusPublished - 24 Feb 2015


  • Acute Coronary Syndrome/epidemiology
  • Antibodies, Anti-Idiotypic/pharmacology
  • Apoptosis/drug effects
  • Apoptosis Regulatory Proteins/metabolism
  • Bcl-2-Like Protein 11
  • CD28 Antigens/deficiency
  • CD4-Positive T-Lymphocytes/drug effects
  • Cell Proliferation/physiology
  • Cells, Cultured
  • Fas-Associated Death Domain Protein/metabolism
  • Homeostasis/physiology
  • Humans
  • MAP Kinase Signaling System/physiology
  • Membrane Proteins/metabolism
  • Phenotype
  • Proteasome Endopeptidase Complex/physiology
  • Proto-Oncogene Proteins/metabolism
  • Recurrence
  • Risk Factors
  • bcl-2-Associated X Protein/metabolism


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