Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis.
Activation-induced cell death (AICD) of lymphocytes is an important mechanism of self-tolerance. In CD4+ T cells, AICD is mediated by the Fas pathway and is enhanced by IL-2. To define the mechanisms of this pro-apoptotic action of IL-2, we analyzed CD4+ T cells from wild-type and IL-2-/- mice expressing a transgenic T cell receptor. T cells become sensitive to AICD after activation by antigen and IL-2. IL-2 increases transcription and surface expression of Fas ligand (FasL) and suppresses transcription and expression of FLIP, the inhibitor of apoptosis. The ability of IL-2 to enhance expression of a pro-apoptotic molecule, FasL, and to suppress an inhibitor of Fas signaling, FLIP, likely accounts for the role of this cytokine in potentiating T cell apoptosis.
Refaeli
Y
Y
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Van Parijs
L
L
London
C A
CA
Tschopp
J
J
Abbas
A K
AK
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D015533:Transcriptional Activation; D019014:fas Receptor / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019014:fas Receptor