The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death.
IL-2-dependent, activation-induced T cell death (AICD) plays an important role in peripheral tolerance. Using CD8+ TCR-transgenic lymphocytes (2C), we investigated the mechanisms by which IL-2 prepares CD8+ T cells for AICD. We found that both Fas and TNFR death pathways mediate the AICD of 2C cells. Neutralizing IL-2, IL-2R alpha, or IL-2R beta inhibited AICD. In contrast, blocking the common cytokine receptor gamma-chain (gamma c) prevented Bcl-2 induction and augmented AICD. IL-2 up-regulated Fas ligand (FasL) and down-regulated gamma c expression on activated 2C cells in vitro and in vivo. Adult IL-2 gene-knockout mice displayed exaggerated gamma c expression on their CD8+, but not on their CD4+, T cells. IL-4, IL-7, and IL-15, which do not promote AICD, did not influence FasL or gamma c expression. These data provide evidence that IL-2 prepares CD8+ T lymphocytes for AICD by at least two mechanisms: 1) by up-regulating a pro-apoptotic molecule, FasL, and 2) by down-regulating a survival molecule, gamma c.
Dai
Z
Z
The Carlos and Marguerite Mason Transplantation Research Center, Renal Division, Department of Medicine, Veterans Affairs Medical Center, Emory University, Atlanta, GA 30033, USA.
Arakelov
A
A
Wagener
M
M
Konieczny
B T
BT
Lakkis
F G
FG
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D007376:Interleukin-2 / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism
D019138:Antibodies, Blocking; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018121:Receptors, Cytokine; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor