Vγ9Vδ2T(γδT)细胞具强大的肿瘤杀伤活性，我们前期报道"体外γδT可有效杀伤AML细胞"，但体内AML往往通过多种机制逃避γδT的免疫杀伤，免疫抑制因子TGF-β在AML的免疫逃逸过程中发挥重要作用。我们发现外源性TGF-β能抑制γδT活化及介导AML逃避免疫杀伤；同时发现γδT杀伤AML的关键是NKG2D与其配体ULBPs识别，TGF-β则显著抑制AML细胞ULBP1和ULBP4表达。因此，推论TGF-β可能通过抑制NKG2D-ULBPs来诱导AML逃避γδT的免疫杀伤。项目应用小分子抑制剂及基因敲除技术，靶向沉默TGF-β/Smads及非Smad通路，明确TGF-β通过Smads或非Smads通路调节NKG2D-ULBPs的作用，探索TGF-β降解ULBPs的机制。全面阐明TGF-β及其下游对γδT识别杀伤AML的负向调控机制，为γδT临床治疗AML、克服免疫逃逸奠定理论基础。

Vγ9Vδ2T cells, the major γδT-cell subset, display a great anti-tumor activity. We previously reported that ex vivo-expanded Vγ9Vδ2T cells could efficiently kill human acute myeloid leukemia cells(AML). However, some immune escape mechanisms protect AML cells from Vγ9Vδ2T attack in vivo, and the transforming growth factor-β (TGF-β) plays a important role in the immune evasion. We found that the addition of TGF-β inhibited Vγ9Vδ2T activation and protect AML cells from killing by Vγ9Vδ2T. Also, the interactions of NKG2D recptor with its ligand ULBPs was necessary in the process of recognizing and killing AML cells by Vγ9Vδ2T; and TGF-β significantly reduced the expression of ULBP1 and ULBP4 in the AML cells. Based on the study above, we hypothesize that TGF-β could protect AML cells from Vγ9Vδ2T attack by inhibiting the interaction of NKG2D-ULBPs. In this project, we will use small molecular inhibitors and RNAi to block of TGF-β/Smads and non-Smads signals，define the effect of down-regulation of NKG2D-ULBPs by TGF-βthrough Smads or non-Smads pathways，and further explore the mechanism of TGF-βinduced shedding of ULBPs by modulating metalloproteinases. This project will not only enrich the understanding of the biological behavior of Vγ9Vδ2T cells, but also develop a new target to conquer immune evasion for AML immunotherapy.