title: c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8(+) memory T-cell survival.
abstract: Cellular inhibitor of apoptosis proteins (c-IAP) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of T cells to costimulation. 4-1BB is a TNF receptor family member that signals via a complex that includes TRAF family members and the c-IAPs to upregulate NF-κB and ERK, and has been implicated in memory T-cell survival. Here, we show that effector and memory T cells from mice expressing a dominant negative E3-inactive c-IAP2 (c-IAP2(H570A)) have impaired signaling downstream of 4-1BB. When infected with lymphocytic choriomeningitis virus, unlike mice in which c-IAPs were acutely downregulated by c-IAP antagonists, the primary response of c-IAP2(H570A) mice was normal. However, the number of antigen-specific CD8(+) but not CD4(+) T cells declined more rapidly and to a greater extent in c-IAP2(H570A) mice than in WT controls. Studies with T-cell adoptive transfer demonstrated that the enhanced decay of memory cells was T-cell intrinsic. Thus, c-IAP E3 activity is required for 4-1BB coreceptor signaling and maintenance of CD8(+) T-cell memory.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Giardino Torchia
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Munitic
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ehydel
authors.initials: E
authors.lastname: Castro
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Herz
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation / Q000821:virology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D007156:Immunologic Memory / Q000235:genetics*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000911:Antibodies, Monoclonal; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: 4-1BB; CD8+ memory T cell; Signal transduction; T-cell memory; Ubiquitination; lymphocytic choriomeningitis virus