IKK antagonizes activation-induced cell death of CD4 super(+) 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 super(+) T cell function. Resistance of aged CD4 super(+) 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 super(+) T cells in aged mice are resistant to activation-induced cell death (AICD) induced by anti-CD3 plus IL-2 stimulation. Furthermore, aged CD4 super(+) T cells display increased IKK beta activity that is associated with attenuated JNK activation. The IKK beta -mediated JNK inactivation in aged CD4 super(+) T cells reduces the degradation of c-FLIP sub(L) and the interaction of Bad with Bcl-X sub(L), but it increases the affinity of Bad for 14-3-3. Pretreatment of aged CD4 super(+) T cells with a specific IKK inhibitor, PS1145, increases the JNK activity blocked by IKK beta and consequently sensitizes the aged CD4 super(+) T cells to AICD. Our study thus demonstrates that IKK antagonizes the AICD of CD4 super(+) T cells in aged mice via inhibition of JNK activation.