Signal transduction pathways in TRAIL-mediated T cell costimulation
Date Issued
2011
Date
2011
Author(s)
Huang, Shih-Chia
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, has been demonstrated to mediate costimulation effect in T cell activation. However, the intra-cellular signaling transduced by TRAIL and the TRAIL costimulatory signaling complementing to TCR stimulation-induced T cell activation remain largely unknown. Aims of this study were to investigate the signaling pathway transduced by TRAIL and the mechanism of TRAIL costimulation to TCR stimulation-induced T cell activation. Our results demonstrated that TRAIL costimulation-induced NF-kappaB activation depended on the PKCtheta-IKK-IkappaB signaling pathway. The PLCgamma1-calcium-NFAT signaling pathway and PI3K-Akt pathway were also activated in TRAIL costimulation. We also demonstrated that TRAIL costimulation amplified TCR proximal kinases signaling. Furthermore, we demonstrated that TRAIL associated with Lck during TRAIL costimulation and the association was required for downstream signaling. DR4-Fc alone stimulation without anti-CD3 mAb also induced the phosphorylation of TCR proximal tyrosine kinases and activated the downstream PI3K-Akt, NFAT and NF-kappaB signaling pathways, but these effects were insufficient for T cell proliferation. Finally, we demonstrated that the TRAIL costimulation induced Lck and PKCtheta recruitment and resulted in lipid rafts reorganization, while these events did not occur in TCR or DR4-Fc alone stimulation. Blocked TRAIL costimulation-induced T cell activation by disruption of lipid rafts indicated the kinases-enriched lipid rafts provided the platform for TRAIL costimulatory signaling integrating into TCR signaling. These results demonstrate that TRAIL costimulation regulates the reorganization of signaling molecules of lipid rafts and then Lck recruitment into lipid rafts integrates the multiple signals from TRAIL and TCR resulting in T cell activation.
Subjects
TRAIL costimulation
Type
thesis
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