Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity

项目总结： 多发性硬化症(MS)是一种影响中枢神经的衰弱的自身免疫性炎症性疾病 中枢神经系统(CNS)，实验性自身免疫性脑脊髓炎(EAE)是最常用的动物 多发性硬化的模型，尽管有新的数据表明TFR-TFH-GC B抗体(Ab)的贡献 对EAE和MS的反应、TFR细胞在疾病发病机制中的作用和抗体的性质 对此的回应在很大程度上仍不得而知。包括TFR细胞在内的效应树突状细胞(ETregs)必须保持其抑制 包括中枢神经系统在内的非淋巴组织的无能表型，以及正在进行的炎症反应。 然而，确保维持无能、血统认同和调节性基因表达的机制 ETregs的活动没有很好地定义。我们最近的出版物揭示了转录的表达 ETregs中的Blimp1因子，包括TfR亚群，对于维持FoxP3的表达和稳定是必不可少的 ETreg抑制活性。Blimp1缺陷的eTregs的促炎潜力促使我们 用髓鞘少突胶质细胞糖蛋白(MOG)诱导的方法检测它们对中枢神经系统自身免疫的影响 EAE模型。我们观察到，FoxP3特异性消融Blimp1的小鼠发生了严重的EAE，未能 恢复，与对照组相比，所有人都死于瘫痪，这反映了不稳定的Blimp1- 缺乏eTregs进入IL-17A/GM-CSF产生效应T细胞(Tef)与糖酵解增强和 失去对TFH-Ab反应的抑制以及异常的小胶质细胞激活。令人惊讶的是，血清中的IgE 抗体滴度与EAE评分呈正相关，这些小鼠中枢神经系统有较多的IgE沉积。 此外，与健康对照组(HC)相比，MS患者循环中的Blimp1+Tregs和Tfr细胞减少 表达较低水平的Blimp1和IL-10，与IgE水平升高相关。我们假设Blimp1 在中枢神经系统自身免疫下，表达通过阻止获得效应器活性和增强eTreg的稳定性 代谢偏斜以及抑制TFH-Ab反应。结合转录、表观基因组和 代谢分析，我们将描绘eTregs，TFR细胞和抗体反应调节的机制 神经炎症和eTregs中Blimp1的丢失如何重塑CNS微环境。建议数 研究将发现Blimp1是一种新的调节因子，对eTreg的稳定性和介导疾病非常重要 中枢神经系统自身免疫期间的恢复。我们的发现指向了一种以前未被认识到的机制 ETreg通过协调对自身免疫环境的反应和维持代谢健康来保持稳定性 对Blimp1的监管。这项研究也有可能揭示TFR细胞未被认识到的作用，并 阐明B细胞和抗体反应(尤其是IgE)在中枢神经系统自身免疫调节中的作用。真知灼见 这些研究可能为制定新的多发性硬化症治疗方法提供关键策略 利用关键T细胞亚群生物学的一个令人惊讶的方面。

PROJECT SUMMARY: Multiple sclerosis (MS) is a debilitating autoimmune inflammatory disease that affects the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model of MS. Although emerging data have suggested the contribution of TFR-TFH-GC B-antibody (Ab) responses to EAE and MS, the contribution of TFR cells to the disease pathogenesis and the nature of Ab response remain largely unknown. Effector Tregs (eTregs) including TFR cells must maintain their suppressive anergic phenotype at non-lymphoid tissues, including the CNS, and during ongoing inflammatory responses. However, the mechanisms that ensure maintenance of anergy, lineage identity and expression of regulatory activity by eTregs are not well defined. Our recent publication has revealed that expression of the transcription factor Blimp1 in eTregs, including the TFR subset, is essential for maintenance of FoxP3 expression and stable eTreg suppressive activity. The pro-inflammatory potential of Blimp1-deficient eTregs has prompted us to examine their impact on the CNS autoimmunity using the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model. We observed that mice with a FoxP3-specific ablation of Blimp1 developed severe EAE, failed to recover and all succumbed to paralysis compared to controls, which reflected conversion of unstable Blimp1- deficient eTregs into IL-17A/GM-CSF-producing effector T-cells (Teff) associated with enhanced glycolysis and loss of suppression on TFH-Ab responses as well as aberrant microglial activation. Surprisingly, serum IgE titers were positively correlated with EAE scores and these mice had more IgE deposition in the CNS. Moreover, compared to healthy controls (HC), MS patients had reduced circulating Blimp1+ Tregs and TFR cells expressing lower levels of Blimp1 and IL-10, associated with elevated IgE levels. We hypothesize that Blimp1 expression enforces eTreg stability under CNS autoimmunity by preventing acquisition of effector activity and metabolic skewing as well as restraining TFH-Ab response. Using combined transcriptomic, epigenomic and metabolic assays, we will delineate the mechanisms by which eTregs, TFR cells and Ab responses regulate neuroinflammation and how loss of Blimp1 in eTregs re-shape the CNS microenvironment. The proposed study will uncover Blimp1 as a new regulator that is important for eTreg stability and for mediating disease recovery during CNS autoimmunity. Our findings point to a previously unrecognized mechanism enforcing eTreg stability by coordinating response to the autoimmune milieu and maintaining metabolic fitness via regulation of Blimp1. This study also has the potential to reveal the unappreciated role of TFR cells, and to clarify the role of B-cells and Ab responses (particularly IgE) in the regulation of CNS autoimmunity. Insights from these studies may provide critical strategies to formulate novel therapeutic approaches to MS by exploiting a surprising aspect of the biology of a critical T-cell subset.