自然杀伤T（NKT）细胞是肝缺血再灌注损伤（IRI）关键的效应性炎细胞。我们在预实验中发现：与野生型NKT细胞不同，缺氧诱导因子（HIF）-2α高表达的NKT细胞不会加重肝IRI，而应用腺苷A2a受体（Adora2a）抑制剂可逆转其免疫耐受效应。我们推测HIF-2升高后作为转录因子激活Adora2a表达而发挥抑炎作用。我们设想通过不同方法获得HIF-2α敲除/高表达的小鼠/人NKT细胞，观察HIF-2α表达变化对细胞表型、功能及Adora2a表达的影响。对NKT细胞中HIF-2与Adora2a之间可能存在的转录调控关系进行分析和确认。对高表达HIF-2α的NKT细胞实施Adora2a RNA干扰，进一步分析细胞表型和功能变化。通过过继输注实验观察NKT细胞HIF-2α/Adora2a表达变化对小鼠肝IRI的影响。本研究将可能揭示NKT细胞功能调控的新机制，并为肝IRI提供新的治疗干预靶点。

Natural Killer T (NKT) cells are critical initiators and effectors of innate immunity in the liver and orchestrate inflammation subsequent to ischemia-reperfusion (IR) injury. We found in preliminary experiments that in contrast to NKT cells from wild-type mice, NKT cells that express high-level hypoxia-inducible factor (HIF)-2α failed to induce inflammatory damage to the liver after IR, which could be reversed by the application of adenosine A2a receptor (adora2a) inhibitors. Based on these observations, we speculate that HIF-2α over-expression might result in transcriptional activation of Adora2a in NKT cells, which accounts for the attenuated inflammatory injury. To prove this theory, we plan to employ genetic methods to obtain mouse/human NKT cells with inactivated or overexpressed HIF-2α, which will be subjected to phenotype and function analyses. Adora2a expression in NKT cells will be assessed by reverse transcription-PCR and immunoblotting. The regulatory relationship between HIF-2 and adora2a in mouse/human NKT cells will be evaluated by promoter studies. Further, the effect of siRNA knockdown of adora2a in HIF-2α-overexpressing NKT cells on their phenotype and function will be observed. Finally, adoptive transfer of NKT cells to Cd1d knockout (NKT cell-deficient) mice will be carried out to evaluate the roles of NKT cell-specific HIF-2α/Adora2a expressions in liver IR injury. These studies may help to promote understanding of the role of HIF-2α in NKT cell function and inflammatory injury after liver IR, which may serve as a novel therapeutic target.