Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4âºCD28null T cells resistant to apoptosis in acute coronary syndrome.
Circulation
; 131(8): 709-20, 2015 Feb 24.
Article
in En
| MEDLINE
| ID: mdl-25527700
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 ANDRESULTS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
CD4-Positive T-Lymphocytes
/
Proto-Oncogene Proteins
/
Apoptosis
/
CD28 Antigens
/
Proteasome Endopeptidase Complex
/
Apoptosis Regulatory Proteins
/
Acute Coronary Syndrome
/
Membrane Proteins
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Circulation
Year:
2015
Document type:
Article
Affiliation country:
Reino Unido