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

• Published in: The Journal of immunology (1950) 2001-08, Vol.167 (3), p.1347-1352
• Main Authors: Chou, A H, Tsai, H F, Lin, L L, Hsieh, S L, Hsu, P I, Hsu, P N
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins; CD3 Complex - immunology; Cells, Cultured; Enzyme Inhibitors - pharmacology; Humans; Imidazoles - pharmacology; Immunoglobulin Fc Fragments - genetics; Immunoglobulin Fc Fragments - metabolism; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interferon-gamma - metabolism; Ligands; Lymphocyte Activation - genetics; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases; Pyridines - pharmacology; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TNF-Related Apoptosis-Inducing Ligand; TRAIL protein; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology; Up-Regulation - drug effects; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.3.1347

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-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 the occurrence of reverse signaling through TRAIL on T cell. The enhanced secretion 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 itself can enhance T cell proliferation after TCR engagement and signal the augmentation of IFN-gamma 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.