許秉寧2018-07-092018-07-092003http://ntur.lib.ntu.edu.tw//handle/246246/25360During T cell activation, there are two signals involved to activate the T cells. One is signal transduced through T cell receptor (TCR), the other is the co-stimulation signal transduced through CD28 or other co-stimulation molecules. Recently there are a number of T cell surface molecules with co-stimulation activity reported including TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L). TRAIL, 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 upregulated in activated T cells. The actual biological function of TRAIL/TRAIL receptor is still not clear. Previous studies in our laboratory, we demonstrated that cross-linking of TRAIL by plate-bound recombinant TRAIL receptor, DR4-Fc fusion protein enhanced T cell proliferation and increased IFN-g production in conjunction with immobilized sub-optimal anti-CD3 stimulation in mouse splenocytes. The increase of T cell proliferation by DR4-Fc was dose-dependent and this effect could be blocked by soluble recombinant TRAIL proteins, indicating the occurrence of co-stimulation effects on T cells via signals transduced through TRAIL (Chou et al., J. Immunol. 167: 1347, 2001). 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-g secretion via a p38-dependent pathway. Our finding further implied the possibility that TRAIL-induced T cell co-stimulation may be involved in T cell activation. The significance of TRAIL co-stimulation and other co-stimulatory molecules in T cell activation is still not clear. Therefore, we further explore the role of TRAIL co-stimulation on T cells activation and the molecular mechanism of signal transduction through TRAIL in T cells. We were able to characterize the T cell subsets responding to TRAIL co-stimulation in T cell activation and to further investigate role of TRAIL induced co-stimulation in the pathogenesis of human auotimmune diseases and we demonstrated that TRAIL costimluate human CD4 T cells and also enhanced the proliferation and IFN-g production in SLE patients CD4 T cells (manuscripts submitted to Arthritis & Rheumatism, in revision). For further exploration of the possible molecular mechanisms of TRAIL-induced T cell co-stimulation, we are studying the possible signaling pathway and the TRAIL associated molecules in transduction of TRAIL reverse signal as well as other co-stimulation signals in T cell activation by using proteomics approach for probing the protein kinase activation in signal transduction during the T cell activation in TRAIL-co-stimulation. We have identified three possible candidate tyrosine phosphoryated proteins in this approach. This study will provide a new approach to address the role and molecular mechanisms of TRAIL induced co-stimulation in T cell activation.application/pdf112506 bytesapplication/pdfzh-TW國立臺灣大學醫學院免疫學研究所TRAILreverse signalhuman CD4 T cellstyrosine kinase[SDGs]SDG3journal articlehttp://ntur.lib.ntu.edu.tw/bitstream/246246/25360/1/912320B002192.pdf