脂肪代谢在SOX13调控γδ T细胞中的作用机制研究

Innate-like lymphocytes γδ T cells play important roles in several immune-responses and pathological processes. The transcriptional factor Sox13, which is the determinant of the γδ versus αβ lineage commitment, involves in the regulation of γδ T cell survival, cytokine-secretion and homing. However, the molecular mechanisms of Sox13-mediated regulation network are limited explored. On the other hand, our knowledge of the involvement of lipid metabolism in γδ T cell behavior keeps unknown. For the first time our preliminary data showed that cholesterol biosynthesis is upregulated during the γδ T cell clonal expansion; applying of lipid biosynthesis inhibitors impedes the proliferation rate of activated γδ T cells; and the luciferase reporter assay demonstrated that the HMG-CoA synthase, cholesterol biosynthesis key enzyme, is the transcriptional target of Sox13. Hence, we proposed to validate the contribution of lipid to γδ T cell behaviors and dissect the regulatory networking by Sox13 in both mice and human (patients) model. The results would also give the similarity between the γδ T cells from two species. This study would provide the clinical immunotherapeutic strategies of γδ T cells theoretic foundation.

类先天免疫细胞γδ T细胞在多种生理病理过程中行使不可代替的重要职能，但脂肪代谢对其生物功能的影响和作用不明。Sox13是决定祖细胞是否分化成为γδ T细胞的决定性转录因子，参与调控γδ T细胞分泌和迁移等重要生物功能。我们前期证明了胆固醇生物合成关键酶HMG-CoA合成酶（HMGCS）是Sox13的转录下游基因；脂肪生物合成抑制剂可抑制γδ T细胞的体外扩增；γδ T细胞发育和活化过程中脂肪代谢关键因子的表达发生显著变化。因此提出 “Sox13通过调控脂肪生物合成参与对γδ T细胞的调控”的假说。本课题拟从基因敲除动物模型和患者样本两方面切入，阐明Sox13对脂肪代谢通路的调控作用；研究脂肪代谢对γδ T细胞发育和活化中扩增、分泌和迁移的影响及相关信号通路；阐明小鼠和人γδ T细胞中脂肪代谢对其影响的异同。本课题γδ T细胞的脂肪代谢重编程可为临床免疫治疗奠定理论依据给出新的线索。

类先天免疫细胞γδ T细胞在肿瘤监测感染等多种生理病理过程中行使不可代替的重要职能，但脂肪代谢对其生物功能的影响和作用不明。我们的结果显示胆固醇是γδ T细胞扩增的必要条件；与扩增相关的胆固醇发生在转录水平而非表观水平；由γδ T细胞关键转录因子SOX13主要通过对胆固醇生物合成途径分子SREBP2和HMGCR的转录调控实现γδ T细胞扩增的调节。项目中建立的对γδ T细胞实现高效转染的纳米辅助病毒转染系统和纳米小RNA转染系统可用于CAR-T，TCR-T等工程化T细胞疗法的制备。