急性炎症中TSC1对树突状细胞的免疫调控效应及机制

Tuberous sclerosis complex 1 (TSC1) plays important roles in tumorigenesis, cells growth and metabolism by negative control of mTOR signaling pathway, and is proving to be a central point in regulating immune function of diverse immune cells. Dendritic cells (DCs), the strongest antigen presenting cell (APC), are crucial in regulating both innate and adaptive immunity, and have been proved to be essential in regulating inflammation. However, the immunomodulatory effects of TSC1 on DCs are still unclear, especially in the acute inflammatory disease. Our preliminary results showed that mice lacking TSC1 in DC increase susceptibility to endotoxic shock, and TSC1-deficient DCs produce increased pro-inflammatory cytokine TNF-α significantly. Under physiological condition, TSC1-deficiency alter the activation state and cytokine production of DCs. These results reveal the important regulatory roles of DC TSC1 in acute inflammation. This research includes the in vivo and in vitro experiments, using DC-TSC1 conditional knockout mice to elucidate the specific regulatory effects of TSC1 on DCs, under physiological and acute inflammatory conditions. This study is expected to provide an experimental basis for clinical evaluation of DC immune function, and for clinical judgement in the diagnosis and prognosis of inflammatory disease.

结节性硬化症基因1（TSC1）通过mTOR途径，在肿瘤发生、细胞生长和新陈代谢中发挥重要作用, 其对免疫细胞的功能调节逐渐成为研究重点。树突细胞（DCs）是抗原提呈能力最强的细胞，在链接天然免疫和适应性免疫应答，介导炎症性免疫调节中发挥重要调控作用。然而，在炎症性疾病中，TSC1对DCs的免疫调节效应仍不清楚。我们前期结果显示，DC TSC1特异性缺失小鼠的内毒素休克症状明显加重，其DC分泌促炎性因子TNFα显著增高。而且，生理条件下TSC1的缺失可以明显改变DC的活化状态及炎性因子分泌等。提示，DC的TSC1基因在急性炎症中发挥重要调控作用。本研究将应用DC的TSC1特异性敲除小鼠及其他遗传模型，采用体内外实验方法，试图明确在正常生理条件和急性炎症中TSC1对DC的免疫调控效应规律，并初步阐明分子机制。该研究有望为临床评价DC的免疫功能和炎性疾病的诊断及预后判断提供实验依据。

结节性硬化症基因1（tuberous sclerosis complex；TSC1）在肿瘤发生、细胞生长和新陈代谢中发挥重要作用,其在免疫细胞中具有关键调控作用。DCs是抗原提呈能力最强的细胞，在调节T细胞应答，介导炎症性免疫调节中发挥重要调控作用，但TSC1在树突状细胞中的调节功能仍不清楚。本项目中我们研究了TSC1在树突状细胞中的调控效应及其依赖的T细胞分化在急性炎症中的作用。结果显示，TSC1基因能够影响cDC1/cDC2的平衡并调节分泌IL-17的Th17细胞的分化，TSC1的缺失会促进CD8+cDC1树突状细胞的分化，进而抑制Th17分化，而其下游mTOR基因的缺失则会促进Th17的分化。我们还发现TSC1介导的DC依赖的Th17细胞的分化在DSS诱导的肠炎和OVA诱导的哮喘中有重要调节作用，TSC1的缺失明显缓解疾病程度。其机制为树突状细胞TSC1的调节了CD4+T细胞中的JNK和STAT3信号途径的活化从而影响T细胞分化。因此，本课题阐述了急性炎症条件下树突状细胞TSC1对T细胞的分化调节效应及机制，为树突状细胞和T细胞参与调控的急性炎症的靶向诊断和治疗提供实验依据。