TNFR1 delivers pro-survival signals that are required for limiting TNFR2-dependent activation-induced cell death (AICD) in CD8+ T cells.

Members of the TNF and TNF receptor (TNFR) superfamily play important roles in the maintenance of homeostasis of the immune system. Furthermore, several members of the TNFR family participate in T-cell activation and sustaining T-cell responses. We have shown that TNFR2 regulates T-cell activation by lowering the activation threshold and providing costimulatory signaling. Furthermore, activated TNFR2(-/-) CD8(+) T cells are highly resistant to activation-induced cell death (AICD). Here, we showed that using anti-TNFR2 antibodies to block TNFR2 on activated WT CD8(+) T cells rendered them resistant to AICD. This resistance of activated TNFR2(-/-) CD8(+) T cells to AICD correlated with the accumulation of TNF receptor-associated factor 2 (TRAF2). Overexpression of TRAF2 by retroviral transfection and knockdown of TRAF2 by small interfering RNA also support this conclusion. Furthermore, neutralizing TNF-α reduced TRAF2 accumulation in activated TNFR2(-/-) CD8(+) T cells and increased their susceptibility to AICD. AICD-resistant TNFR2(-/-) CD8(+) T cells expressed elevated levels of phosphorylated IκBα and higher DNA-binding activity of the p65 NK-κB subunit and neutralization of TNF-α blocked this increase. Therefore, in activated TNFR2(-/-) CD8(+) T cells, TNFR1 functions as a survival receptor by utilizing high intracellular levels of TRAF2 to promote IκBα phosphorylation and NF-κB activation.