Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4(+)CD28(null) T Cells Resistant to Apoptosis in Acute Coronary Syndrome

Article

关键词: IMMUNE-SYSTEM;    BH3-ONLY PROTEINS;    REGULATORS BIM;    DEATH;    FAS;    LYMPHOCYTES;    SURVIVAL;    BCL-2;    ATHEROSCLEROSIS;    AUTOIMMUNITY;   

DOI  :  10.1161/CIRCULATIONAHA.114.013710

来源: SCIE

【 摘 要 】

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 CD28null 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.

【 授权许可】

Free