title: Mechanisms of necroptosis in T cells.
abstract: Cell populations are regulated in size by at least two forms of apoptosis. More recently, necroptosis, a parallel, nonapoptotic pathway of cell death, has been described, and this pathway is invoked in the absence of caspase 8. In caspase 8-deficient T cells, necroptosis occurs as the result of antigen receptor-mediated activation. Here, through a genetic analysis, we show that necroptosis in caspase 8-deficient T cells is related neither to the programmed necrosis as defined by the requirement for mitochondrial cyclophilin D nor to autophagy as defined by the requirement for autophagy-related protein 7. Rather, survival of caspase 8-defective T cells can be completely rescued by loss of receptor-interacting serine-threonine kinase (Ripk) 3. Additionally, complementation of a T cell-specific caspase 8 deficiency with a loss of Ripk3 gives rise to lymphoproliferative disease reminiscent of lpr or gld mice. In conjunction with previous work, we conclude that necroptosis in antigen-stimulated caspase 8-deficient T cells is the result of a novel Ripk1- and Ripk3-mediated pathway of cell death.
authors.affiliation: Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ch'en
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Tsau
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D053181:Caspase 8 / Q000502:physiology*; D002470:Cell Survival; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000502:physiology; D009336:Necrosis / Q000276:immunology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; D053181:Caspase 8; D000071193:Autophagy-Related Protein 7