c‐IAP ubiquitin protein ligase activity is required for 4‐1BB signaling and CD8+ memory T‐cell survival |
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| Authors: | Maria Letizia Giardino Torchia Ivana Munitic Ehydel Castro Jasmin Herz Dorian B. McGavern Jonathan D. Ashwell |
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| Affiliation: | 1. Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;2. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA |
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| 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‐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. |
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| Keywords: | 4‐1BB CD8+ memory T cell lymphocytic choriomeningitis virus Signal transduction T‐cell memory Ubiquitination |
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