Th细胞免疫失衡及细胞因子紊乱与SLE的发生发展密切相关。本课题组前期设计制备了拮抗IL23p19和IL23p40亚基的两个重组蛋白thIL12rb1和rhIL23RCHR，但在治疗SLE模型鼠时存在明显差异。经蛋白组学修饰谱比较发现，转录因子Blimp1巴豆酰化修饰水平的差异是最主要的因素，并与新近发现的Tfr细胞分化相关。本项目拟以thIL12rb1调节Blimp1巴豆酰化修饰发挥治疗作用为切入点，采用IP-MS确定thIL12rb1影响Blimp1巴豆酰化的修饰位点；突变并转染naïveT细胞考察Tfr细胞表型改变；在条件性敲除酰化酶基因小鼠观察Blimp1的功能改变，明确thIL12rb1疗效与酰化水平及酰化酶的相关性，阐明Blimp1的巴豆酰化动态修饰与调控Tfh/Tfr细胞平衡的关系，比较IL23p19亚基与p40亚基间的功能差异，为设计治疗SLE的新型蛋白类药物奠定基础。

The development of SLE is closely related to Th cell immune imbalance and cytokine disorders. Our previous study has designed two recombinant proteins, thIL12rb1 and rhIL23RCHR, which antagonize the IL23p19 and IL23p40 subunits, but there were significant differences in the efficacy of the SLE model mice. During our extensive study on proteomic modification of Blimp1, we found that the difference in the level of crotonylation of Blimp1 was the most important factor and correlated with the newly discovered Tfr cell activity. In our study, crotonylation of Blimp1 regulated by thIL12rb1 played a therapeutic role. IP-MS was used to determine the modification site of blimp1 crotonylation by thIL12rb1. The phenotypic changes of Tfr cells were investigated by transfecting naïve T cells by mutation. Through observing the functional changes of Blimp1 in mice with conditional knockout acylase gene, the correlation between the efficacy of thIL12rb1 and the acylation level was clarified, and the molecular characteristics and effect relationship of Blimp1 dynamic modification were elucidated. We aim to delineate completely the relationship between dynamic modification of Blimp1 crotonylation and regulation of plasticity differentiation of Tfh/Tfr balance, then defined the functional differences between IL23 p19 subunit and IL23 p40 subunit, laying a foundation for the design of novel protein drugs for the treatment of SLE.