title: Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity.
abstract: Caspase-8 (casp8) is required for extrinsic apoptosis, and mice deficient in casp8 fail to develop and die in utero while ultimately failing to maintain the proliferation of T cells, B cells, and a host of other cell types. Paradoxically, these failures are not caused by a defect in apoptosis, but by a presumed proliferative function of this protease. Indeed, following mitogenic stimulation, T cells lacking casp8 or its adaptor protein FADD (Fas-associated death domain protein) develop a hyperautophagic morphology, and die a programmed necrosis-like death process termed necroptosis. Recent studies have demonstrated that receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3 together facilitate TNF-induced necroptosis, but the precise role of RIPKs in the demise of T cells lacking FADD or casp8 activity is unknown. Here we demonstrate that RIPK3 and FADD have opposing and complementary roles in promoting T-cell clonal expansion and homeostasis. We show that the defective proliferation of T cells bearing an interfering form of FADD (FADDdd) is rescued by crossing with RIPK3(-/-) mice, although such rescue ultimately leads to lymphadenopathy. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that FADD, casp8, and RIPK3 are all essential for clonal expansion, contraction, and antiviral responses. Finally, we demonstrate that caspase-mediated cleavage of RIPK1-containing necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis in the face of death receptor signaling. These studies highlight the "two-faced" nature of casp8 activity, promoting clonal expansion in some situations and apoptotic demise in others.
authors.affiliation: Department of Molecular Biology and Biochemistry, Institute for Immunology, University of California, Irvine, CA 92697, USA.
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Lu
authors.forename: Brian M
authors.initials: BM
authors.lastname: Weist
authors.forename: Bram J
authors.initials: BJ
authors.lastname: van Raam
authors.forename: Brett S
authors.initials: BS
authors.lastname: Marro
authors.forename: Long V
authors.initials: LV
authors.lastname: Nguyen
authors.forename: Prathna
authors.initials: P
authors.lastname: Srinivas
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Bell
authors.forename: Keith A
authors.initials: KA
authors.lastname: Luhrs
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lane
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Craig M
authors.initials: CM
authors.lastname: Walsh
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000821:virology*; D049109:Cell Proliferation; D002470:Cell Survival; D003433:Crosses, Genetic; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000821:virology; D006706:Homeostasis / Q000276:immunology*; D007109:Immunity / Q000276:immunology*; D008297:Male; D051379:Mice; D006517:Murine hepatitis virus / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse