TY - JOUR
T1 - c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8+ memory T-cell survival
AU - Giardino Torchia, Maria Letizia
AU - Munitic, Ivana
AU - Castro, Ehydel
AU - Herz, Jasmin
AU - Mcgavern, Dorian B.
AU - Ashwell, Jonathan D.
N1 - Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - 4-1BB
KW - CD8 memory T cell
KW - Lymphocytic choriomeningitis virus
KW - Signal transduction
KW - T-cell memory
KW - Ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=84940962244&partnerID=8YFLogxK
U2 - 10.1002/eji.201445342
DO - 10.1002/eji.201445342
M3 - Article
C2 - 26096449
AN - SCOPUS:84940962244
VL - 45
SP - 2672
EP - 2682
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 9
ER -