TRAIL引發T細胞共活化刺激作用的訊息傳遞機制

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)是TNF分子族群中的成員之一，已經被證實可在T細胞活化時引起共活化作用。然而，對於TRAIL的細胞內訊息傳遞，以及其引發的共活化刺激訊息如何輔助T細胞受器的刺激作用，進而造成T細胞活化目前仍然未知。本論文的目的在於研究TRAIL的訊息傳遞路徑，並且瞭解TRAIL共活化刺激作用如何幫助T細胞受器刺激作用造成T細胞活化的分子機制。我們發現在TRAIL共活化刺激中，能夠藉由引起PKCθ-IKK-IκB 訊息傳遞路徑的活化來引發NF-κB的活化。此外，TRAIL共活化刺激也能引起PLCγl-calcium-NFAT訊息傳遞路徑與PI3K-Akt訊息傳遞路徑的活化。我們也發現TRAIL共活化刺激能放大T細胞受器近端激酶的訊息傳遞。更進一步地，在TRAIL共活化刺激中，TRAIL能夠和Lck交互作用，並且這樣的交互作用能夠影響TRAIL共活化刺激所引起的訊息傳遞。然而，在沒有刺激T細胞受器而只有單獨刺激TRAIL時，也能夠引起T細胞受器近端激酶以及下游PI3K-Akt訊息傳遞路徑、NFAT與NF-κB的活化。雖然單獨刺激TRAIL能夠引起類似於TRAIL共活化刺激時的訊息傳遞反應，但是不足以造成T細胞活化。最後，我們發現在TRAIL共活化刺激下，能夠引起Lck與PKCθ進入脂質筏(lipid rafts)內，造成脂質筏的重組，而這樣的現象在單獨刺激T細胞受器或是TRAIL都不會發生。擾亂脂質筏的結構能夠阻止TRAIL共活化刺激所引起的T細胞活化，這表示TRAIL共活化刺激訊息是在脂質筏內將訊息匯聚到T細胞受器的訊息傳遞內。因此我們的結論是在TRAIL共活化刺激下，能夠引起訊息分子進入脂質筏內，而Lck進入脂質筏內能匯聚TRAIL的訊息與T細胞受器的訊息，最後造成T細胞活化。

關鍵字

TRAIL共活化作用

並列摘要

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.

並列關鍵字

TRAIL costimulation

參考文獻

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TRAIL引發T細胞共活化刺激作用的訊息傳遞機制

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