Enhanced proliferation and increased IFN-gamma production in T cells by signal transduced through TNF-related apoptosis-inducing ligand

TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel m ember of TNF superfamily, induces apoptosis in transformed cell lines of di verse origin. TRAIL is expressed in most of the cells, and the expression i s up-regulated in activated T cells. Four receptors for TRAIL have been ide ntified, and there is complex interplay between TRAIL and TRAIL receptors i n vivo. The actual biological function of TRAIL/TRAIL receptor is still not clear. Growing evidence has demonstrated that members of TNF superfamily t ransduce signals after engagement with their receptors. Cross-linking of TR AIL by plate-bound rTRAIL receptor, death receptor 4-Fc fusion protein enha nced T cell proliferation and increased IFN-gamma production in conjunction with immobilized suboptimal anti-CD3 stimulation in mouse splenocytes. The increase of T cell proliferation by death receptor 4-Fc was dose dependent , and this effect could be blocked by soluble rTRAIL proteins, indicating t he occurrence of reverse signaling through TRAIL on T cell. The enhanced se cretion of IFN-gamma mediated via TRAIL could be blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in inducing apoptosis by binding to the death receptors, TRAIL its elf can enhance T cell proliferation after TCR engagement and signal the au gmentation of IFN-gamma secretion via a p38-dependent pathway. This provide s another example of reverse signaling by a member of TNF superfamily. In c onclusion, our data suggest that TRAIL can itself transduce a reverse signa l, and this may shed light on the biological function of TRAIL.