IKK antagonizes activation-induced cell death of CD4+ T cells in aged mice via inhibition of JNK activation

T cell dysfunction is the primary immunologic abnormality associated with aging Many age-related defects stem from a decline in CD4(+) T cell function Resistance of aged CD4(+) T cells to apoptosis is associated with autoimmune and infectious diseases Previous studies suggest that I kappa B kinase (IKK) may be a key player in cell survival via its inhibition of c-Jun N-terminal protein kinase (JNK) activation However the role of IKK-mediated JNK inactivation in the age-related apoptosis of T cells is unclear Here we report that splenic CD4(+) T cells in aged mice are resistant to activation-Induced cell death (AICD) induced by anti-CD3 plus IL-2 stimulation Furthermore aged CD4+ T cells display Increased IKK beta activity that is associated with attenuated JNK activation The IKK beta-mediated JNK inactivation in aged CD4(+) T cells reduces the degradation of c-FLIPL and the Interaction of Bad with BcI-X-L but It Increases the affinity of Bad for 14-3-3 Pretreatment of aged CD4+ T cells with d specific IKK inhibitor PSI 145 Increases the JNK activity blocked by IKK beta and consequently sensitizes the aged CD4(+). T cells to AICD Our study thus demonstrates that IKK antagonizes the AICD of CD4(+) T cells in aged mice via inhibition of JNK activation (C) 2010 Elsevier Ltd All rights reserved