title: Up-regulation of c-FLIPshort and reduction of activation-induced cell death in CD28-costimulated human T cells.
abstract: Efficient activation of antigen-specific T cells requires co-stimulatory signals provided e.g. by CD28. Re-exposure to antigen and CD28 co-stimulation reduces activation-induced cell death (AICD) and increases the number of T cells performing effector functions. AICD is mediated predominantly by CD95 (APO-1/Fas) and its cognate ligand (CD95L). In an in vitro model system, using human peripheral activated T cells, we demonstrate here that costimulation prevents CD95L expression. Moreover, we show that co-stimulation reduces the activity of the CD95 death-inducing signaling complex and procaspase-8 activation. In parallel, co-stimulation strongly increases expression of the short form of the FLICE-inhibitory protein c-FLIPshort and of Bcl-xL. These data provide important new insight into the molecular mechanisms of apoptosis resistance in co-stimulated T cells.
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg.
authors.forename: S
authors.initials: S
authors.lastname: Kirchhoff
authors.forename: W W
authors.initials: WW
authors.lastname: Müller
authors.forename: M
authors.initials: M
authors.lastname: Li-Weber
authors.forename: P H
authors.initials: PH
authors.lastname: Krammer
mesh_terms: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000032:analysis; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D018448:Models, Immunological; D016853:Muromonab-CD3 / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology*
chemical_list: C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018106:CD28 Antigens; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051020:bcl-X Protein; D019014:fas Receptor; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases