title: Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells.
abstract: TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-gamma/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27(Kip1) nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G(1) arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.
authors: Division of Neuroimmunology, Department of Neurology, Charité University Hospital, Neuroscience Research Center, 10098 Berlin, Germany.
authors: Jan D
authors: JD
authors: Lünemann
authors: Sonia
authors: S
authors: Waiczies
authors: Stefan
authors: S
authors: Ehrlich
authors: Uwe
authors: U
authors: Wendling
authors: Bibiane
authors: B
authors: Seeger
authors: Thomas
authors: T
authors: Kamradt
authors: Frauke
authors: F
authors: Zipp
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens / Q000276:immunology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D016193:G1 Phase / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D016196:S Phase / Q000276:immunology; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D002118:Calcium