髓源性抑制细胞通过PD-L1诱导的TGF-β参与HIV-1慢性期患者免疫重建失败的机制研究

免疫重建失败的HIV-1患者有较高的并发症和病死率，目前缺乏有效的治疗手段。髓源性抑制细胞（MDSC）在负向调节机体免疫反应中起重要作用，但其在HIV-1免疫重建中的作用及其分子机制尚不清楚。我们前期研究发现HIV-1慢性期升高的粒细胞样(G)-MDSC与疾病进展相关；其上调的PD-L1与CD4+T细胞表达的PD-1相关；介导MDSC抑制T细胞免疫的调控分子TGF-β基因转录水平显著升高。基于以上发现，提出“MDSC可能通过PD-L1诱导的TGF-β影响HIV-1慢性期患者的免疫功能重建”的研究假说。为验证此假说，本项目首先借助临床样本，明确MDSC与免疫重建的相关性；然后拟通过细胞分选、细胞培养、PD-L1通路阻断及TGF-β信号抑制，探讨介导MDSC抑制CD4+T细胞免疫反应的潜在机制。本研究有望阐明MDSC在HIV-1慢性期患者免疫重建失败中的关键作用，为临床治疗提供新思路。

Immunological recovery failure associates with increased morbidity and mortality in HIV-1 positive patients, and currently lacks effective treatment. Myeloid-derived suppressor cells (MDSC) play an important role in negatively regulating immune response, but its role in HIV-1 immune reconstruction and the molecular mechanism is unclear. We recently discovered increase levels of granulocytic myeloid-derived suppressor cells (G-MDSC) in immunological non-responders (INR) compared to immunological responders (IR), which is correlated to the disease progression and might suppress CD4+ T-lymphocytes recovery. Still, its underlying molecular regulatory mechanism remains to be further investigated.. Based on our preliminary experiment, we noted that: i) elevated programmed cell death ligand 1 (PD-L1) expression on G-MDSC was positively correlated with PD-1 on CD4+ T-cells; ii) among several potential molecules by which G-MDSC suppress CD4 response, the mRNA expression of TGF-β was significantly higher in INR G-MDSC compared to that of healthy controls. Therefore, we supposed that PD-L1 signaling induced TGF-β secretion through G-MDSC which suppress CD4+ T-cell response in INR. . Herein, we aim to extend our work in order to address the role of G-MDSC in the pathogenesis of poor immune reconstitution in chronically HIV-1 infected patients. First, we will analyze the correlation between G-MDSC and immunological recovery using clinical specimens, Second, G-MDSC and CD4+ T cells will be isolated, cocultured, PD-L1 pathway blockade, inhibition of TGF-β signaling pathway to see the effect of restoration of G-MDSC-mediated suppression of CD4 functions. . In summary, through this study, we will unveil the new mechanisms of immunological recovery failure, which may provide a potential target for developing therapeutic intervention.