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

效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献

• 批准号: 10837917
• 负责人: Jianmei Wu Leavenworth
• 金额: $ 23.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10837917
• 关键词: Ablation; Adopted; Affect; Animal Model; Antibodies; Antibody Affinity; Antibody Response; Antigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological Assay; Biology; CNS autoimmunity; Cells; Central Nervous System; Data; Deposition; Development; Disease; Disease Progression; Ensure; Epigenetic Process; Eragrostis; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Generations; Genetic; Glycolysis; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; IL17 gene; IgE; Immune response; Impairment; Infection; Inflammatory; Inflammatory Response; Interleukin-10; Maintenance; Mediating; Metabolic; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Nature; Paralysed; Pathogenesis; Phenotype; Publications; Recovery; Regulation; Regulatory T-Lymphocyte; Role; Secondary to; Serum; Shapes; Structure of germinal center of lymph node; T-Lymphocyte Subsets; TFRC gene; Testing; Tissues; Vaccination; anergy; comparison control; defined contribution; disorder control; effector T cell; epigenomics; glial activation; insight; metabolic fitness; microbial; multiple sclerosis patient; neuroinflammation; novel therapeutic intervention; oligodendrocyte-myelin glycoprotein; prevent; programs; response; restraint; tertiary lymphoid organ; transcription factor; transcriptomics

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.

项目概要： 多发性硬化症（MS）是一种影响中枢神经的衰弱性自身免疫性炎症性疾病 实验性自身免疫性脑脊髓炎（EAE）是最常用的动物 虽然新出现的数据表明TFR-TFH-GC B-抗体（Ab）的贡献， 对EAE和MS的反应，TFR细胞对疾病发病机制的贡献以及Ab的性质 反应仍然很大程度上未知。包括TFR细胞在内的效应细胞TFR（eTFR）必须维持其抑制性TFR表达。 在非淋巴组织，包括中枢神经系统，以及在持续的炎症反应过程中的无能表型。 然而，确保维持无反应性、谱系身份和调控基因表达的机制， eTectoris的活动没有很好地定义。我们最近发表的文章揭示了转录的表达 eTFR中的Blimp 1因子，包括TFR亚群，对于维持FoxP 3的表达和稳定性至关重要。 eTreg抑制活性。Blimp 1缺陷型eTdR的促炎潜力促使我们 使用髓鞘少突胶质细胞糖蛋白（MOG）诱导的CNS自身免疫检查它们的影响。 EAE模型。我们观察到，FoxP 3特异性阻断Blimp 1的小鼠发生了严重的EAE， 与对照组相比，恢复和所有瘫痪，这反映了不稳定的Blimp 1- 将缺乏eTeff的细胞转化为产生IL-17 A/GM-CSF的效应T细胞（Teff），与糖酵解增强相关， 对TFH-Ab应答的抑制丧失以及异常的小胶质细胞活化。令人惊讶的是，血清IgE 滴度与EAE评分呈正相关，并且这些小鼠在CNS中具有更多的IgE沉积。 此外，与健康对照组（HC）相比，MS患者的循环Blimp 1 + TFR和TFR细胞减少 表达较低水平的Blimp 1和IL-10，与升高的IgE水平相关。我们假设Blimp 1 表达通过防止获得效应子活性来加强eTreg在CNS自身免疫下的稳定性， 代谢偏斜以及抑制TFH-Ab应答。使用联合转录组学、表观基因组学和 代谢分析，我们将描绘的机制，通过eTfls，TFR细胞和抗体反应调节 神经炎症和Blimp 1的损失如何在eTectorre塑造CNS微环境。拟议 研究将揭示Blimp 1作为一种新的调节因子，对eTreg稳定性和介导疾病非常重要 CNS自身免疫期间恢复。我们的发现指出了一种以前未被认识到的机制， 通过协调对自身免疫环境的反应并通过维持代谢适应性来维持eTreg稳定性 Blimp 1的规则。这项研究也有可能揭示TFR细胞未被重视的作用， 阐明B细胞和Ab应答（特别是IgE）在CNS自身免疫调节中的作用。见解 这些研究可能提供关键的战略，制定新的治疗方法，以MS， 利用了一个关键T细胞亚群的生物学的惊人方面。

项目成果

AIMing 2 promote lupus by targeting helpers.

• DOI: 10.1002/ctm2.844
• 发表时间: 2022-05
• 期刊: Clinical and translational medicine
• 影响因子: 10.6

Lineage Reprogramming of Effector Regulatory T Cells in Cancer.

• DOI: 10.3389/fimmu.2021.717421
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Dixon ML;Leavenworth JD;Leavenworth JW
• 通讯作者: Leavenworth JW

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.

• DOI: 10.1186/s12974-021-02076-4
• 发表时间: 2021-01-19
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Luo L;Hu X;Dixon ML;Pope BJ;Leavenworth JD;Raman C;Meador WR;Leavenworth JW
• 通讯作者: Leavenworth JW

Structure-Activity Relationship Study of Momordica Saponin II Derivatives as Vaccine Adjuvants.

• DOI: 10.1021/acs.jmedchem.2c01087
• 发表时间: 2022-11-10
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Kim, Hyunjung;Bai, Di;Ghosh, Sadashib;Franks, Michael L.;Wang, Xifeng;Yan, Cheng;Liu, Zheng;Zhang, Ping;Michalek, Suzanne M.;Leavenworth, Jianmei W.;Wang, Pengfei
• 通讯作者: Wang, Pengfei

Analysis of the In Vivo Function of Follicular Regulatory T (TFR) Cells in the Regulation of Antibody Response.

滤泡调节 T (TFR) 细胞在抗体反应调节中的体内功能分析。

• DOI: 10.1007/978-1-0716-2647-4_1
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Luo,Lin;Leavenworth,JianmeiW
• 通讯作者: Leavenworth,JianmeiW