Lipid raft assembly and Lck recruitment in TRAIL costimulation mediates NF-κB activation and T cell proliferation.

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-kappa B pathway. TRAIL induced the NF-kappa B pathway by phosphorylation of inhibitor of kappa B factor kinase and protein kinase C theta 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-kappa B 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 theta. These results demonstrate that TRAIL costimulation mediates NF-kappa B 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-kappa B-dependent signals from the TCR and TRAIL in T lymphocytes. The Journal of Immunology, 2011, 186: 931-939.