TNFR1 is the primary signaling receptor that initiates the majority of inflammatory responses classically attributed to TNF. In contrast, TNFR2 is important in modulating TNFR1-mediated signaling by inducing the depletion of TNF receptor-associated factor 2 (TRAF2) and cellular

inhibitor of apoptosis1 (c-IAP1) proteins and accelerates TNFR1-dependent activation of caspase-8 12, 13. TNFR superfamily members can be classified into two main groups, death domain (DD)-containing receptors such as TNFR1, and TRAF-binding receptors such as TNFR2 that lack a DD 1, 2. Signaling via TNFR1 can have two outcomes. After binding of TNF, TNFR1 recruits the DD-containing adaptor molecule TNFR1-associated DD protein, which functions as a platform to recruit additional signaling molecules for the assembly of alternative Tanespimycin signaling complexes. One complex involves receptor-interacting protein and TRAF2

which links ligand-induced signaling to the activation of the transcription factors NF-κB and AP1 14–17. Another signaling complex is formed dependent on the internalization of activated TNF/TNFR1 complexes. During endocytosis FADD and caspase-8 are recruited to form the death inducing Dorsomorphin signaling complex resulting in TNF-induced apoptosis 2, 14, 15. In this study, we investigated the impact of TNFR2 on regulating cell death or survival as a result of TNFR1 signaling. We tested the hypothesis that in the absence of TNFR2, signaling via TNFR1 would promote cell survival by promoting NF-κB activation by the following mechanism. It is known Resveratrol that TNFR2 signaling leads to the degradation of TRAF2 13. We postulated that in TNFR2-deficient cells, TRAF2 degradation is prevented and the relatively high intracellular levels of TRAF2 in these cells would promote TNFR1-induced NF-κB activation and cell survival. Our results support

this hypothesis. We showed that blocking TNFR2 signaling in anti-CD3+IL-2-activated WT CD8+ T cells resulted in elevated intracellular TRAF2 levels and an increase in their resistance to AICD. Furthermore, blocking anti-TNF-α antibodies significantly reduced TRAF2 accumulation in activated TNFR2−/− CD8+ T cells and increased their susceptibility to AICD. We found that AICD-resistant cells expressed elevated level of phosphorylated IκBα and higher DNA binding activity of the p65 NF-κB subunit, providing further support of our hypothesis that TNFR1 functions as a pro-survival receptor in TNFR2-deficient CD8+ T cells. The activation and differentiation of T cells are dependent on TCR-antigen interaction and the engagement of multiple molecules on the APC by receptors on the T cell. Previously, we demonstrated that TNFR2 not only lowers the threshold for T-cell activation but also provides early costimulatory signals during T-cell activation 6–8.