Enhanced Proliferation and Increased IFN-γ Production in T Cells by Signal Transduced Through TNF-Related Apoptosis-Inducing Ligand

Abstract

TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel member of TNF superfamily, induces apoptosis in transformed cell lines of diverse origin. TRAIL is expressed in most of the cells, and the expression is up-regulated in activated T cells. Four receptors for TRAIL have been identified, and there is complex interplay between TRAIL and TRAIL receptors in vivo. The actual biological function of TRAIL/TRAIL receptor is still not clear. Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. Cross-linking of TRAIL by plate-bound rTRAIL receptor, death receptor 4-Fc fusion protein enhanced T cell proliferation and increased IFN-γ 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 the occurrence of reverse signaling through TRAIL on T cell. The enhanced secretion of IFN-γ 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 itself can enhance T cell proliferation after TCR engagement and signal the augmentation of IFN-γ secretion via a p38-dependent pathway. This provides another example of reverse signaling by a member of TNF superfamily. In conclusion, our data suggest that TRAIL can itself transduce a reverse signal, and this may shed light on the biological function of TRAIL.

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

“…Our previous reports on RANK and DcR3 have indicated additional players by these soluble receptors in the regulation of cell function, and confirmed the concept of reverse signaling. [33][34][35]58 We demonstrated that DcR3 could modulate the differentiation and maturation of DC from CD14 þ monocytes. 33 Moreover, DcR3 can suppress macrophage differentiation from monocytes, but enhance monocyte adhesion.…”

Mouse T cells receive costimulatory signals from LIGHT, a TNF family member

“…29,30 TRAIL cross-linking also induces p38 MAPK activation. 19 We examined the mechanisms of for 24 hours were cross-linked with anti-CD3 and anti-CD28 hamster mAb followed by goat-anti-hamster IgG. After fixing with 3.7% formalin, the cells were stained with anti-human LIGHT mAb (clone 1.2.2) followed by PE-F(ab)Ј2 of goat anti-human IgG, along with FITC-anti-Thy1.2.…”

“…[16][17][18] Crosslinking of TRAIL by its solid-phase death receptor 4 increases IFN-␥ production and T-cell proliferation. 19 Whether LIGHT can reversely transduce signals into T cells has not been assessed.…”

T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

“…For example, in vitro data indicate that TRAIL can either suppress or costimulate T cell responses depending on whether it acts as a ligand or as a receptor, respectively (17)(18)(19). In vivo studies using TRAIL knockout (KO) mice or TRAIL blockade have demonstrated exacerbation of disease in murine models of collagen-induced arthritis (20), diabetes (21)(22)(23), and experimental autoimmune encephalomyelitis (24).…”