浆细胞样树突状细胞(pDCs)在刚地弓形虫感染引起的急性炎症中抑制Th1型细胞因子风暴的机制研究

Cytokine storm has serious harmfulness in infectious diseases. The immunopathology is major mediated by local production of Th1-type cytokine storm during acute infection with Toxoplasma gondii (T. gondii). Recently studies have shown that pDCs play a protective role during virus infection by modulation of adaptive immune response, but its regulatory mechanism is not clear, and its role in T. gondii infection induced Th1-type cytokine storm is not clear. Our preliminary experiment found that depletion of pDCs resulted in an exacerbation of Th1-type cytokine storm by T. gondii infection, and negatively regulate Th1 responses related molecules expression were up-regulated in pDCs, these imply that pDCs negative regulate Th1-type cytokine storm under infected state. Using modern immunology experimental technique combined with pDCs gene conditional knockout mice to study and in-depth understanding the regulatory mechanisms of pDCs in negatively regulate Th1-type cytokine storm during acute infection with T. gondii. This study will provide potential targets of therapeutic strategy in control infectious diseases induced Th1-type cytokine storm.

细胞因子风暴在感染性疾病中具有严重危害性，刚地弓形虫感染导致组织免疫病理损伤主要是由Th1型细胞因子风暴介导的。有研究表明pDCs在病毒感染时可能通过调控适应性免疫应答对感染组织免疫病理损伤起到保护作用，pDCs在弓形虫感染引起的Th1型细胞因子风暴中作用是不清楚的。我们前期研究发现，pDCs缺失后加重弓形虫感染引起的以Th1为主的细胞因子风暴，并且感染过程中pDCs表达的负向调控Th1反应的相关分子水平明显上调，提示感染状态下，pDCs对Th1型细胞因子风暴发挥负向调控作用。据此推测，弓形虫感染状态下pDC可通过自身细胞行为学和分子水平改变，而对Th1型细胞因子风暴发挥负向调控作用。本课题将以现代免疫学方法结合pDCs条件性基因敲除小鼠为实验平台，深入探讨pDCs在刚地弓形虫感染过程中负向调控Th1型细胞因子风暴的分子机制，为控制感染性疾病中Th1型细胞因子风暴的治疗策略提供潜在靶点。

细胞因子风暴在感染性疾病中具有严重危害性，但其调控机制不清楚。我们研究发现，弓形虫感染导致pDCs细胞数量显著性减少，pDC缺失加重弓形虫感染引起的以Th1为主的细胞因子风暴，因此我们推测pDC在感染状态下对Th1的过度活化发挥负向调控作用。研究结果发现在感染早期，骨髓pDCs的发育就被改变，在感染急性期，由于骨髓pDCs的前体细胞数量的减少进而导致骨髓里pDCs数量显著性减少，从而导致脾脏里pDCs的数量显著性减少。感染状态下，pDCs的发育收到FLT3L/E2-2信号通路调控，而pDCs可能通过PD1/PDL1免疫检测点来负向调控CD4+T细胞分泌IFN-γ的水平，进而避免感染诱导的Th1型细胞因子过度分泌。