SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Kovalcsik, E; Antunes, RF; Baruah, P; Kaski, JC; Dumitriu, IE (2015) Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome. Circulation, 131 (8). pp. 709-720. ISSN 1524-4539 https://doi.org/10.1161/CIRCULATIONAHA.114.013710
SGUL Authors: Dumitriu, Ingrid Elena Kaski, Juan Carlos

[img]
Preview
PDF Published Version
Available under License ["licenses_description_publisher" not defined].

Download (2MB) | Preview

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.

Item Type: Article
Additional Information: This is a non-final version of an article published in final form in Kovalcsik, E; Antunes, RF; Baruah, P; Kaski, JC; Dumitriu, IE (2015) Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome. Circulation, 131 (8). pp. 709-720
Keywords: T-lymphocytes, allergy and immunology, apoptosis, atherosclerosis, Acute Coronary Syndrome, Antibodies, Anti-Idiotypic, Antigens, CD28, Apoptosis, Apoptosis Regulatory Proteins, CD4-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Fas-Associated Death Domain Protein, Homeostasis, Humans, MAP Kinase Signaling System, Membrane Proteins, Phenotype, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Recurrence, Risk Factors, bcl-2-Associated X Protein, CD4-Positive T-Lymphocytes, Cells, Cultured, Humans, Recurrence, Proteasome Endopeptidase Complex, Membrane Proteins, Antigens, CD28, Proto-Oncogene Proteins, Antibodies, Anti-Idiotypic, Risk Factors, Apoptosis, Cell Proliferation, MAP Kinase Signaling System, Homeostasis, Phenotype, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Fas-Associated Death Domain Protein, Acute Coronary Syndrome, allergy and immunology, apoptosis, atherosclerosis, T-lymphocytes, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology, 1117 Public Health And Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: Circulation
ISSN: 1524-4539
Language: eng
Dates:
DateEvent
24 February 2015Published
19 December 2014Published Online
12 December 2014Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
PG/10/50/28434British Heart FoundationUNSPECIFIED
PG/14/18/30724British Heart FoundationUNSPECIFIED
PubMed ID: 25527700
Web of Science ID: WOS:000350286300010
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107600
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.114.013710

Actions (login required)

Edit Item Edit Item