c‐IAP ubiquitin protein ligase activity is required for 4‐1BB signaling and CD8+ memory T‐cell survival

• Published in: European journal of immunology Vol. 45; no. 9; pp. 2672 - 2682
• Main Authors: Giardino Torchia, Maria Letizia, Munitic, Ivana, Castro, Ehydel, Herz, Jasmin, McGavern, Dorian B., Ashwell, Jonathan D.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2015
• Subjects: 4‐1BB; Adoptive Transfer; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis - genetics; Apoptosis - immunology; Baculoviral IAP Repeat-Containing 3 Protein; CD8+ memory T cell; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - virology; Cell Survival - genetics; Cell Survival - immunology; Cells, Cultured; Female; Gene Expression Regulation; Immunologic Memory - genetics; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - immunology; Inhibitor of Apoptosis Proteins - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Count; Lymphocytes; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - pathology; Lymphocytic Choriomeningitis - virology; lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - immunology; Mice; Mice, Transgenic; Mutation; NF-kappa B - genetics; NF-kappa B - immunology; Rodents; Signal Transduction; T cell receptors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; T‐cell memory; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; CD8+ memory T cell; Signal transduction; 4-1BB; Ubiquitination; lymphocytic choriomeningitis virus; T-cell memory
• DOI: 10.1002/eji.201445342
• ISSN: 0014-2980

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‐IAP2H570A) 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‐IAP2H570A 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‐IAP2H570A 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.