The NF-kappaB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells.
Apoptosis of activated T cells is critical for the termination of immune responses. Here we show that adjuvant-stimulated dendritic cells secrete cytokines that prime activated T cells for survival and analyze the roles of the NF-kappaB regulator Bcl-3 and the proapoptotic Bcl-2 family members Bim and Puma. Bcl-3 overexpression increased survival, and activated bcl-3-/- T cells died abnormally rapidly. Cytokines from adjuvant-stimulated dendritic cells induced Bcl-3, but survival through cytokine priming was Bcl-3-independent. Apoptosis inhibition by Bcl-3 involved blockade of Bim activation, because Bim was overactivated in Bcl-3-deficient cells, and Bcl-3 failed to increase survival of bim-/- T cells. However, adjuvants increased survival also in Bim-deficient T cells. This Bim-independent death pathway is at least in part regulated by Puma, as shown by analysis of puma-/- and noxa-/- T cells. IL-1, IL-7, and IL-15 primed T cells for survival even in the absence of Bim or Puma. Our data define interrelations and a Bim-independent pathway to activated T cell death.
Bauer
Anette
A
Institute for Medical Microbiology, Technical University Munich, Trogerstrasse 9, D-81675 Munich, Germany.
Villunger
Andreas
A
Labi
Verena
V
Fischer
Silke F
SF
Strasser
Andreas
A
Wagner
Hermann
H
Schmid
Roland M
RM
Häcker
Georg
G
D000276:Adjuvants, Immunologic; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081242:B-Cell Lymphoma 3 Protein; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; D000081242:B-Cell Lymphoma 3 Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000631345:Bcl3 protein, mouse; D007378:Interleukins; D008565:Membrane Proteins; D016328:NF-kappa B; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins