The high levels of intracellular TRAF2 in TNFR2−/− cells then promote the pro-survival function of TNFR1, which is mediated by the activation of the canonical NF-κB pathway, which involves phosphorylation of the IκBα inhibitory subunit and NF-κB activation, as evidenced by an increase in the binding of the p65 NF-kB subunit to the NF-κB consensus site. Since the pro-survival function of TNFR1 in TNFR2−/−
CD8+ T cells, which express WT levels of TNFR1, is blocked by neutralizing anti-TNF-α antibodies, this observation indicates that TNFR1 functions as a pro-survival receptor in TNFR2−/− CD8+ T cells. These studies also illustrate the importance of cross talk between TNFR1 and TNFR2 in determining survival versus death of activated T cells. They high throughput screening also suggest novel mechanisms for regulating T-cell responses by regulating the activity of TNFR1 and TNFR2 at various stages of T-cell Trichostatin A cell line activation. For instance, specific inhibition of TNFR2 function at later stages of T-cell activation may prolong the survival of activated T cells by promoting the pro-survival function of TNFR1. We noted that the addition of a neutralizing TNF-α
antibody reduced the proliferative response of anti-CD3-stimulated WT CD8+ to almost basal level, a level that was significantly lower than that observed for cultures of TNFR2−/− CD8+ T cells activated under the same conditions (Fig. 5B). It is unlikely that the amount of neutralizing anti-TNF-α antibody in cultures of TNFR2−/− CD8+ T cells activated Sitaxentan under these conditions was insufficient for neutralizing
TNF-α since anti-CD3-activated WT and TNFR2−/− CD8+ T cells produced similar amounts of TNF-α. We have previously shown that anti-CD3-activated TNFR2−/− CD8+ T cells produced very little IL-2 compared with similarly activated WT CD8+ T cells 7. IL-2 has been shown to sensitize anti-CD3-activated CD8+ T cells to AICD 22 via a Fas/Fas ligand-dependent mechanism 23, 24. Interestingly, anti-CD3-activated TNFR2−/− CD8+ T cells are also highly resistant to Fas/Fas ligand-induced cell death 9. It remains to be determined whether TNFR2 regulates Fas/FasL-induced cell death in CD8+ T cells by a TRAF2-dependent or independent mechanism. Nevertheless, regardless of the mechanism by which TNFR2 regulates Fas/FasL-induced cell death, it is likely that the lower proliferative response observed for WT CD8+ T cells as a result of TNF-α neutralization is due to higher susceptibility to Fas/Fas ligand-induced cell death as a result of higher production of IL-2 in these cultures. We have previously reported that the resistance of activated TNFR2−/− CD8+ T cells to AICD correlates with high expression levels of pro-survival molecules such as Bcl-2, surviving and CD127 10. In a more recent study, we showed that the resistance of activated TNFR2−/− CD8+ T cells to AICD correlated with more effective protection against the growth of syngeneic tumor cells.
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