title: Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome.
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.
  
  
  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.
authors.affiliation: From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom.
authors.forename: Edit
authors.initials: E
authors.lastname: Kovalcsik
authors.affiliation: From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom.
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Antunes
authors.affiliation: From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom.
authors.forename: Paramita
authors.initials: P
authors.lastname: Baruah
authors.affiliation: From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Kaski
authors.affiliation: From the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, Cranmer Terrace, London, United Kingdom. i.dumitriu@sgul.ac.uk.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
mesh_terms: D054058:Acute Coronary Syndrome / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D018106:CD28 Antigens / Q000172:deficiency*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012008:Recurrence; D012307:Risk Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D018106:CD28 Antigens; D053200:Fas-Associated Death Domain Protein; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex
keywords: T-lymphocytes; allergy and immunology; apoptosis; atherosclerosis