title: Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.
abstract: Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim(-/-) mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8(-/-) T cells, Bim(-/-) T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim(-/-) T cells and restrains autoimmunity in Bim(-/-) mice.
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors: Toshiyuki
authors: T
authors: Bohgaki
authors: Julien
authors: J
authors: Mozo
authors: Leonardo
authors: L
authors: Salmena
authors: Elzbieta
authors: E
authors: Matysiak-Zablocki
authors: Miyuki
authors: M
authors: Bohgaki
authors: Otto
authors: O
authors: Sanchez
authors: Andreas
authors: A
authors: Strasser
authors: Anne
authors: A
authors: Hakem
authors: Razqallah
authors: R
authors: Hakem
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency*; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D053181:Caspase 8 / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053181:Caspase 8