부산대학교 도서관

Aim: Atherosclerosis is now widely recognized as a disease with an underlying immune deregulation. Patients with coronary atherosclerosis that develop myocardial infarction (MI) have an expansion of a unique subset of T lymphocytes, the CD4+CD28null (CD28null) T cells, characterized by the lack of the CD28 co-stimulatory receptor. These cells have a pro-inflammatory and cell-lytic phenotype. Patients harbouring high numbers of CD28null T have increased risk of recurrent severe acute coronary events (i.e. MI) and unfavourable prognosis. Why CD28null T cells accumulate preferentially in patients with MI compared to patients with stable angina (SA) and healthy individuals is currently unknown. T cell homeostasis is maintained by elimination of unwanted T cells via apoptotic cell death. We hypothesized that apoptosis pathways that mediate elimination of T cells are dysregulated in CD28null T cells in patients with MI. Our aim was to investigate molecules involved in apoptosis regulation in CD28null T cells in patients with coronary atherosclerosis (MI and SA).Methods: Levels of pro-apoptotic (i.e. Fas, FasL, Bim and Bax) and anti-apoptotic (Bcl-2, Bcl-xL) proteins were measured in patients with MI (n=25) and SA patients (n=18) using flow-cytometry. Apoptosis sensitivity of CD28null T cells to the Fas-ligating antibody CH11 and C2-ceramide was measured with annexin-V and 7-AAD.Results: Pro-apoptotic molecules Fas, Bim and Bax were dramatically reduced on CD28null T cells in patients with MI, whilst anti-apoptotic molecules Bcl-2 and Bcl-xL were similar in CD28null and CD28+ T cells. Notably, CD28null T cells in patients with MI showed significantly lower Bim and Bax levels compared to CD28null T cells in SA patients. We found that CD28null T cells in MI patients were resistant to apoptosis induction via Fas-ligation or ceramide. Furthermore, we show that proteasomal inhibition restores apoptosis sensitivity of CD28null T cells in patients with MI.Conclusion: We show that CD28null T cells in patients with MI 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. Furthermore, we propose a novel mechanism that implicates the proteasome as a key regulator of apoptosis sensitivity of CD28null T cells in patients with MI. 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 patients with coronary atherosclerosis.