γδT17-MDSCs调控轴在胃MALT淋巴瘤微环境免疫稳态失衡中的作用及机制研究

Regional immune dysfunction of gastric mucosa induced by Helicobacter pylori (HP) provides the pathogenetic background of gastric MALT lymphoma. Most studies have been focusing on roles of adaptive immunity in gastric MALT lymphoma. However, the functions of innate immunity in the pathogenesis of gastric MALT lymphoma are still poorly understood. As important innate immune cells, γδT17 cells markedly accumulate in gastric mucosa, which play important roles in regional immune homeostasis. It has been observed that IL-17, the effector molecule of γδT17, was significantly increased in gastric MALT lymphoma microenvironment, suggesting that γδT17 might participate in the pathogenesis of gastric MALT lymphoma. In this program, we will take regional immunity of gastric mucosa as the breakthrough point to explore the regulatory network of γδT17, MDSCs, CD8+ T cells and their roles in the development of gastric MALT lymphoma. We firstly intend to investigate infiltration and clinical significance of γδT17, MDSCs and CD8+ T cells in gastric MALT lymphoma microenvironment in vitro. Moreover, we will establish murine gastric MALT lymphoma models with TCRδ-/-, IL-17-/- and wild-type mice, and dynamically monitor tumor growth as well as reginal immune homeostasis imbalance after HP infection. Besides, we plan to isolate primary cells from gastric MALT lymphoma mice to study the roles and underlying molecular mechanisms of γδT17 in MDSCs recruitment, MDSCs in γδT17 polarization and regulation of CD8+ T cells in the pothegenesis of gastric MALT lymphoma. The project aims to shed light on functions and mechanisms of γδT17-MDSCs axis in immune dysregulation of gastric MALT lymphoma microenvironment and provide novel therapic targets for gastric MALT lymphoma.

胃MALT淋巴瘤发生发展与HP感染导致的胃粘膜区域免疫稳态失衡密切相关。γδT17细胞在胃粘膜中高度富集，参与维持胃粘膜区域免疫稳态，其效应分子IL-17在胃MALT淋巴瘤中高表达，提示γδT17在该病中起重要作用。本项目拟以胃粘膜区域免疫为切入点，探讨γδT17、MDSCs、CD8+ T细胞间调控网络及其在胃MALT淋巴瘤发生发展中的作用。研究胃MALT淋巴瘤微环境中γδT17、MDSCs、CD8+ T细胞的浸润及其临床意义；构建TCRδ-/-、IL-17-/-及野生型胃MALT淋巴瘤小鼠模型，动态监测HP感染后成瘤情况及区域免疫稳态失衡；分离模型鼠原代细胞，深入研究γδT17对MDSCs招募、MDSCs对γδT17极化及其对CD8+ T细胞的调控作用及机制。预期目标的实现将揭示γδT17-MDSCs调控轴在胃MALT淋巴瘤免疫失衡中的作用机制，为该病提供新的治疗靶点。

胃MALT淋巴瘤发生发展与HP感染导致的胃粘膜区域免疫稳态失衡密切相关。作为粘膜固有免疫重要组成细胞，γδT17在肿瘤免疫逃逸中发挥关键作用。研究发现γδT17在胃粘膜中高度富集，其效应分子IL-17在胃MALT淋巴瘤中高表达，提示γδT17在该病中起重要作用。本项目拟以胃MALT淋巴瘤区域免疫微环境为切入点，探索γδT17、MDSC及其细胞因子间的相互调控网络。我们研究发现，H.f菌能够被TLR2等受体识别，激活下游NF-κB信号通路，引起一系列炎性因子表达升高，进而介导胃粘膜局部γδT17细胞比例升高。H.f菌感染小鼠可以诱导γδT17细胞应答，γδT17细胞通过分泌IL-17，招募更多MDSC到达胃局部，后者可能通过抑制T细胞功能，参与H.f菌感染后的免疫调控，介导肿瘤免疫逃逸。我们进一步研究发现，胃MALT淋巴瘤组织中γδT17、MDSC细胞比例较对照组明显升高，Arg-1、i-NOS较对照组明显增多，胃MALT淋巴瘤患者外周血中γδT17细胞比例明显降低。以上结果证实局部免疫稳态失衡与胃MALT淋巴瘤发生发展密切相关。另外我们还研究发现NHL患者外周血中存在γδT17减少，并且免疫负调细胞MDSC、Treg细胞显著升高，提示NHL患者免疫稳态失衡，可能参与NHL的发生发展。胃粘膜局部从炎症到肿瘤发展过程中MDSC表达逐渐升高，提示MDSC募集与免疫失衡和疾病进展密切相关。本项目阐明了γδT17-MDSC调控轴在胃MALT淋巴瘤免疫失衡中的重要作用，对于发现新的靶点、改善胃MALT淋巴瘤患者预后具有重要的临床意义。