title: Necroptotic signaling in adaptive and innate immunity.
abstract: The vertebrate immune system is highly dependent on cell death for efficient responsiveness to microbial pathogens and oncogenically transformed cells. Cell death pathways are vital to the function of many immune cell types during innate, humoral and cellular immune responses. In addition, cell death regulation is imperative for proper adaptive immune self-tolerance and homeostasis. While apoptosis has been found to be involved in several of these roles in immunity, recent data demonstrate that alternative cell death pathways are required. Here, we describe the involvement of a programmed form of cellular necrosis called "necroptosis" in immunity. We consider the signaling pathways that promote necroptosis downstream of death receptors, type I transmembrane proteins of the tumor necrosis factor (TNF) receptor family. The involvement of necroptotic signaling through a "RIPoptosome" assembled in response to innate immune stimuli or genotoxic stress is described. We also characterize the induction of necroptosis following antigenic stimulation in T cells lacking caspase-8 or FADD function. While necroptotic signaling remains poorly understood, it is clear that this pathway is an essential component to effective vertebrate immunity.
authors.affiliation: Institute for Immunology, Department of Molecular Biology and Biochemistry, 3215 McGaugh Hall, University of California, Irvine, Irvine, CA 92697-3900, United States.
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Lu
authors.affiliation: Institute for Immunology, Department of Molecular Biology and Biochemistry, 3215 McGaugh Hall, University of California, Irvine, Irvine, CA 92697-3900, United States.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Institute for Immunology, Department of Molecular Biology and Biochemistry, 3215 McGaugh Hall, University of California, Irvine, Irvine, CA 92697-3900, United States. Electronic address: cwalsh@uci.edu.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Walsh
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D018448:Models, Immunological; D009336:Necrosis / Q000276:immunology* / Q000378:metabolism; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8
keywords: Apoptosis; Cell death; Immune system; Immunity; Necroptosis; T cells