IL-21/IL-21R信号通路介导的滤泡辅助性T细胞活化在2型糖尿病中的作用及机制研究

Previous research on type 2 diabetes (T2D) mainly focus on T cell induced immune responses and insulin resistance. New evidences have indicated that B cell induced immune responses also play critical roles in the development of T2D. Our preliminary data supported this by showing that B cells from obese subjects and obese diabetic subjects exhibited more activated phenotype and showed higher production of proinflammatory cytokines than healthy subjects. However, the mechanism of B cell activation and its role in T2D remain unknown. Follicular helper T cell (Tfh) is a novel T cell subtype and can support B cell function. Our preliminary results have reported increased Tfh frequency in T2D. We hypothesize that dysregulation of Tfh in T2D may be the reason of B cell activation. In this study, we will investigate the maturation and activation of Tfh in T2D patients and healthy controls by using flow cytometry; we will examine the function of Tfh in T2D through in vitro experiments; we will test the effect of IL-21/IL-21R pathway on regulating the function of Tfh in T2D patients; we will also test effect of Tfh and IL-21 pathway on T2D in mouse model. This research sheds lights on understanding the pathogenesis of T2D from a novel angle. It might help to develop a new biological agents for the treatment of diabetes, ameliorating the progress of diabetes and improving the treatment effects. We believe it is a project with clinical meaning and social value.

2型糖尿病（T2D）的既往研究多集中于T细胞介导的细胞免疫与胰岛素抵抗。最新研究发现，B细胞介导的体液免疫在T2D中亦占有重要地位。本课题组前期研究发现：T2D患者促炎症反应表型的B细胞明显增多，分泌抗体能力上升。但是，B细胞异常活化的机制及在T2D中的作用不明。辅助性滤泡T细胞（Tfh）是一种新型的T细胞亚型，可促进B细胞成熟和分化。我们前期研究表明，T2D患者的Tfh数量上升且亚型比例失调。故推断T2D患者的Tfh功能失调可导致B细胞活化。本课题拟分析Tfh在T2D中的亚型分布、成熟活化和功能改变；阐明Tfh在T2D中的免疫调节机制，明确是否通过IL-21/IL-21R途径导致细胞功能改变；最后在小鼠模型上验证Tfh可能的治疗作用。本课题从免疫细胞的角度阐释T2D的发病机理，将为控制T2D病情进展、提高治疗效果提供新的思路和治疗手段。

2型糖尿病（T2D）的既往研究多集中于T细胞介导的细胞免疫与胰岛素抵抗。最新研究发现，B细胞介导的体液免疫在T2D中亦占有重要地位。本课题组研究发现：T2D患者促炎症反应表型的B细胞明显增多，分泌抗体能力上升。辅助性滤泡T细胞（Tfh）是一种新型的T细胞亚型，在促进B细胞成熟和分化中有重要作用。本课题通过分析Tfh在T2D中的亚型分布、成熟活化和功能改变，发现T2D患者的Tfh数量上升且亚型比例失调，其中CD4+CXCR5+亚型T细胞在非肥胖型T2D患者中比例升高，这些细胞分泌IFN-γ更多，分泌IL-4和IL-17更少；此外，和CCR6-CD4+CXCR5+T细胞相比，CCR6+CD4+CXCR5+T细胞可以促进B细胞分泌更多的IgG。总之，这些研究表明非肥胖型T2D患者CD4+CXCR5+T细胞比例更高，Th17表达更多，并且和胰岛自身抗体阳性有关。本课题从免疫细胞的角度阐释T2D的发病机理，将为控制T2D病情进展、提高治疗效果提供新的思路和治疗手段。