γδTreg通过MAPK/NF-κB通路抑制树突状细胞成熟在急性移植物抗宿主病中的作用和机制研究

急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植的重要并发症。调节性γδT细胞（γδTreg）是具有负向免疫调控功能的新细胞亚群。我们通过去甲基化作用和单细胞转录组测序建立了γδTreg诱导扩增分选体系，并发现其能负向调控aGVHD而不影响移植物抗白血病效应，但相关机制尚不明确。我们前期研究发现，γδTreg体内抑制树突状细胞（DC）成熟是其中的关键环节，但γδTreg对不同来源DC具有差异调控功能，且与γδTreg/DC比例相关，分子机制有待阐明。进一步的体外研究发现，γδTreg抑制DC成熟主要由MAPK/NF-κB通路介导，提示该通路的调控是体内γδTreg对不同来源DC抑制功能不同的关键。本项目拟通过体内外实验深入研究γδTreg抑制DC成熟在负向调控aGVHD中的作用，探讨MAPK/NF-κB通路在其中的调控作用，为γδTreg应用于aGVHD的防治提供理论基础和优化靶点。

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Regulatory γδT cells (γδTreg) is a newly discovered cell subset with negative immunoregulation function. We have established an induction, amplification, and sorting system of γδTreg through demethylation effect and single cell RNAseq, and found that γδTreg can negatively regulate aGVHD without affecting the graft-versus-leukemia effect, but the mechanism is still unclear. Preliminary experiments showed that the inhibition of dendritic cells (DC) maturation by γδTreg in vivo is the key step. But the immunosuppressive effects of γδTreg on DC from different organs were different, which is related to the γδTreg/DC ratio, and the molecular mechanism needed be to further elucidated. Further study in vitro showed that MAPK/NF-κB pathway was involved in the inhibition of DC maturation by γδTreg, which suggested that the regulation of this pathway in vivo is the key to the different inhibitory effects of γδTreg on DC from different organs. The aim of this project is to study the role of γδTreg in suppressing DC maturation in the negative regulation of aGVHD, and to explore the regulatory role of MAPK/NF-κB pathway in it. The results of this project will lay the foundation for γδTreg in the prevention and treatment of aGVHD and also provide targets for optimizing the clinical application of γδTreg.