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

Maria Letizia Giardino Torchia, Ivana Munitic, Ehydel Castro, Jasmin Herz, Dorian B. Mcgavern, Jonathan D. Ashwell

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish
Pages (from-to)2672-2682
Number of pages11
JournalEuropean Journal of Immunology
Issue number9
StatePublished - Sep 1 2015


  • 4-1BB
  • CD8 memory T cell
  • Lymphocytic choriomeningitis virus
  • Signal transduction
  • T-cell memory
  • Ubiquitination


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