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Circulation. 2015 Feb 24;131(8):709-20. doi: 10.1161/CIRCULATIONAHA.114.013710. Epub 2014 Dec 19.

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

Author information

1
From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom.
2
From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom. i.dumitriu@sgul.ac.uk.

Abstract

BACKGROUND:

The number of CD4(+)CD28(null) (CD28(null)) 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 CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28(null) T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28(null) T cells in ACS.

METHODS AND RESULTS:

We found that CD28(null) 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 CD28(null) T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS.

CONCLUSIONS:

We show that CD28(null) 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 CD28(null) T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control the apoptosis sensitivity of CD28(null) T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients.

KEYWORDS:

T-lymphocytes; allergy and immunology; apoptosis; atherosclerosis

[Indexed for MEDLINE]

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