Soluble TNF-α but not transmembrane TNF-α sensitizes T cells for enhanced activation-induced cell death

Abstract

In addition to its proinflammatory effects, TNF-α exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-α (tmTNF) and soluble TNF-α (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4+ T cells from wtTNF, TNF-α-deficient (TNF−/−) and TNF−/− mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activation-induced cell death (AICD), however, was significantly attenuated in tmTNF and TNF−/−, compared with wtTNF CD4+ T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF−/− CD4+ T cells to levels seen in wtTNF CD4+ T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4+ T cells for AICD was also evident in an in vivo model of adoptively transferred CD4+ T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.