Proteasome-Mediated Reduction in Pro-Apoptotic Molecule Bim Renders CD4+CD28null T Cells Resistant to Apoptosis in Acute Coronary Syndrome
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 harbouring high numbers of CD28null T cells have increased risk of recurrent severe acute coronary events and unfavourable 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 due to a dramatic reduction in pro-apoptotic molecules Bim, Bax and Fas in CD28null T cells, whilst anti-apoptotic 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 harbour marked defects in molecules that regulate T cell apoptosis, which tips the balance in favour of anti-apoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that inhibition of proteasomal activity allows CD28null T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control apoptosis sensitivity of CD28null T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients.
- Received October 10, 2014.
- Revision received December 1, 2014.
- Accepted December 12, 2014.