IL-4 potentiates activated T cell apoptosis via an IL-2-dependent mechanism.
Activation-induced cell death (AICD) of T cells is one of the major mechanisms of peripheral tolerance. The regulation of AICD by IL-4 is poorly understood. In this study, we report that AICD in IL-4-deficient T cells is significantly reduced compared with that in wild-type T cells. This impaired AICD correlates with the failure to induce degradation of cellular FLIP. IL-4-mediated enhancement of AICD and cellular FLIP degradation requires a Janus kinase/STAT-6 signaling pathway. Unexpectedly, these effects of IL-4 could be blocked by a neutralizing anti-IL-2 Ab, and addition of rIL-2 could completely restore the defective AICD in IL-4-deficient T cells. Furthermore, IL-4 regulates the T cell thresholds for IL-2 signaling during AICD. These data suggest that IL-4 promotes AICD via an IL-2-dependent mechanism.
Zhang
Jian
J
Section of Biochemistry and Molecular Biology, Department of Orthopedic Surgery, Rush University at Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. jzhang1@rush.edu
Bárdos
Tamás
T
Shao
Qing
Q
Tschopp
Jurg
J
Mikecz
Katalin
K
Glant
Tibor T
TT
Finnegan
Alison
A
D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D053222:Fas Ligand Protein; D007376:Interleukin-2 / Q000502:physiology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism
D000276:Adjuvants, Immunologic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D019014:fas Receptor; D015847:Interleukin-4