title: Lipid raft assembly and Lck recruitment in TRAIL costimulation mediates NF-κB activation and T cell proliferation.
abstract: The TNF-related apoptosis-inducing ligand was shown to provide a costimulatory signal that cooperates with the TCR/CD3 complex to induce T cell proliferation and cytokine production. Although a number of signaling pathways were linked to the TCR/CD3 complex, it is not known how these two receptors cooperate to induce T cell activation. In this study, we show that TRAIL-induced costimulation of T cells depends on activation of the NF-κB pathway. TRAIL induced the NF-κB pathway by phosphorylation of inhibitor of κB factor kinase and protein kinase C in conjunction with anti-CD3. Furthermore, we demonstrated that TRAIL costimulation induced phosphorylation of the upstream TCR-proximal tyrosine kinases, Lck and ZAP70. Ligation of the TRAIL by its soluble receptor, DR4-Fc, alone was able to induce the phosphorylation of Lck and ZAP70 and to activate the NF-κB pathway; however, it was insufficient to fully activate T cells to support T cell proliferation. In contrast, TRAIL engagement in conjunction with anti-CD3, but not TRAIL ligation alone, induced lipid raft assembly and recruitment of Lck and PKC. These results demonstrate that TRAIL costimulation mediates NF-κB activation and T cell proliferation by lipid raft assembly and recruitment of Lck. Our results suggest that in TRAIL costimulation, lipid raft recruitment of Lck integrates mitogenic NF-κB-dependent signals from the TCR and TRAIL in T lymphocytes.
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Huang
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tsai
authors.forename: Horng-Tay
authors.initials: HT
authors.lastname: Tzeng
authors.forename: Hsiu-Jung
authors.initials: HJ
authors.lastname: Liao
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
mesh_terms: D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism* / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis / Q000502:physiology
chemical_list: D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human