Abstract
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.
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 language | English |
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Pages (from-to) | 709-720 |
Number of pages | 12 |
Journal | Circulation |
Volume | 131 |
Issue number | 8 |
Early online date | 19 Dec 2014 |
DOIs | |
Publication status | Published - 24 Feb 2015 |
Keywords
- 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