Tfh cells: linking the gut microbiota to a gut-distal autoimmune disease

Tfh 细胞：将肠道微生物群与肠道远端自身免疫性疾病联系起来

• 批准号: 10541253
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 49.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541253
• 关键词: Ablation; Address; Affect; Antigens; Area; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Lymphocytes; Bacteria; Blood; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chronic; Cre lox recombination system; Data; Dendritic Cells; Deoxyglucose; Development; Disease; Dissection; Distal; Dose; Exhibits; Exposure to; Functional disorder; Glucose; Glycolysis; Helper-Inducer T-Lymphocyte; Human; IL17 gene; IL2RA gene; Immune; Immune System Diseases; Immunity; Immunoglobulin A; Immunologic Markers; Industrialization; Inflammatory; Interleukin-2; K/BxN model; Learning; Link; Lupus; Lymphoid Tissue; Maps; Mediating; Microbe; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Patients; Peripheral; Peyer' s Patches; Phenotype; Production; Public Health; Regulatory T-Lymphocyte; Reporting; Rheumatoid Arthritis; Risk; Role; Severities; Signal Transduction; Site; Systemic disease; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Work; antagonist; autoimmune arthritis; cancer therapy; cell motility; cell type; chemokine receptor; commensal bacteria; dysbiosis; exhaust; exhaustion; follow-up; gut microbes; gut microbiota; human microbiota; humanized mouse; imprint; inhibitor; microbiota; migration; mouse model; new epidemic; novel; pathobiont; potential biomarker; programs; receptor; response; systemic autoimmunity; theories

PROJECT SUMMARY. Dysbiosis (gut microbiota imbalance) has been implicated in gut-distal autoimmune diseases, such as autoimmune arthritis and lupus.!However, the mechanisms by which gut microbiota impact gut-distal/systemic diseases remain largely unknown. T follicular helper (Tfh) cells specialize in helping B cells, and excessive Tfh responses put patients at risk for autoimmunity. Previously, using the K/BxN autoimmune arthritis model, we showed that gut commensal segmented filamentous bacteria (SFB) induce arthritis by driving differentiation and egression of Peyer's patch (PP) Tfh cells into systemic sites, boosting systemic Tfh responses and exacerbating arthritis. SFB induce PP Tfh differentiation by limiting IL-2 access to CD4+ T cells, thereby enhancing Bcl-6, the Tfh cell master regulator, in a dendritic cell (DC)-dependent manner. Notably, many autoimmune patients exhibit IL-2 deficiency, and low-dose IL-2 provides promising autoimmune therapy. We will determine how microbiota-mediated IL-2 deficiency affects both Tfh-related autoimmunity and IL-2 therapy (Aim 1). We will first examine whether Tfh cell induction by SFB relies on CD25-expressing DCs, quenching IL-2 secreted by CD4+ T cells at the T-B cell border. We will track single cell migration between gut and systemic sites and identify circulating Tfh cells as well as peripheral helper T (Tph) cells, a new cell type found in RA that also helps B cells, in blood as a potential biomarker for dysbiosis-induced autoimmunity in our mouse model and patients with rheumatoid arthritis (RA). We reported that SFB promote K/BxN autoimmunity by inducing dual TCR-expressing Th17 cells. Our new data also show the presence of IL-17+ Tfh-like cells in SFB+ K/BxN mice. We hypothesize that microbiota promote the conversion of Th17 into Tfh cells in PPs, which enhances autoimmune arthritis (Aim 2). We will examine plasticity by Th17 fate mapping and use single cell TCR analysis to analyze if a microbiota-skewed dual TCR repertoire promotes autoimmunity. We will use the Cre-loxP system to address the function of Th17-derived Tfh cells. Chronic antigen (Ag) exposure causes T cell exhaustion. Autoimmune T cells also encounter chronic Ag, but the role of exhaustion in autoimmunity is less clear. Prolonged IL-2 exposure induces Blimp-1 and depletes cellular glucose to promote T cell exhaustion, which is countered by Bcl-6. As SFB reduce IL-2 signaling and induce Bcl-6, we theorize that microbiota trigger autoimmunity by inhibiting T and/or Tfh cell exhaustion (Aim 3). We will ablate exhaustion marker Tim-3 to study exhaustion's contribution to autoimmunity. We will examine if IL-2 and microbiota inversely control Tfh glycolysis to modulate T cell exhaustion. We will also test if gut-derived Tfh and Tph cells are less exhausted and have increased cellular glucose in human RA. In conclusion, we will learn how microbiota induce gut-distal diseases by altering gut Tfh cell plasticity and exhaustion. We expect IL-2 therapy works by inhibiting Tfh cells, and that cTfh and Tph cells may serve as a dysbiotic autoimmune signal. This proposal is unique as it focuses on mucosal immunity and its link to systemic autoimmunity. !

项目总结。肠道微生物区系失调(肠道微生物区系失衡)与肠道末端自身免疫有关 疾病，如自身免疫性关节炎和狼疮。然而，肠道微生物区系影响的机制 肠道末端/系统疾病在很大程度上仍不为人所知。T滤泡辅助细胞(TFH)专门帮助B细胞， 过度的TFH反应使患者面临自身免疫的风险。以前，使用K/BxN自身免疫 在关节炎模型上，我们发现肠道共生节段性丝状细菌(SFB)通过 促进Peyer‘s Patch(PP)Tfh细胞向全身部位分化和渗出，促进全身Tfh 反应和加重关节炎。SFB通过限制IL-2对CD4+T细胞的访问诱导PP Tfh分化， 从而以树突状细胞(DC)依赖的方式增强TFH细胞主调节因子Bc l-6。值得注意的是， 许多自身免疫患者表现出IL-2缺乏，小剂量IL-2提供了有前景的自身免疫治疗。 我们将确定微生物区系介导的IL-2缺乏如何影响TFH相关自身免疫和IL-2 治疗(目标1)。我们将首先研究SFB对TFH细胞的诱导是否依赖于表达CD25的DC， 猝灭T-B细胞交界处的CD4+T细胞分泌的IL-2。我们将跟踪单个细胞在肠道之间的迁移 和系统位置，并鉴定循环中的Tfh细胞以及一种新的细胞类型--外周辅助T(TPH)细胞 在RA中发现，也有助于B细胞，血液中作为一个潜在的生物标记物，在我们的 类风湿性关节炎(RA)小鼠模型和患者。我们报道了SFB促进K/BxN自身免疫 通过诱导双表达TCR的Th17细胞。我们的新数据也显示了IL-17+Tfh样细胞在 SFB+K/BxN小鼠。我们假设在PPS中微生物区系促进Th17向TFH细胞的转化， 可增强自身免疫性关节炎(目标2)。我们将通过Th17命运图来检查可塑性，并使用单个 细胞TCR分析，以分析微生物区系倾斜的双TCR谱系是否促进自身免疫。我们将使用 Cre-loxP系统来解决Th17来源的Tfh细胞的功能。慢性抗原(Ag)暴露导致 T细胞耗竭。自身免疫T细胞也会遇到慢性抗原，但耗竭在自身免疫中的作用是 不太清楚。长期IL-2暴露诱导Blimp-1并耗尽细胞葡萄糖促进T细胞 精疲力竭，这是由Bcl-6对抗的。由于SFB减少了IL-2信号并诱导了Bcl-6，我们从理论上认为 微生物区系通过抑制T和/或TFH细胞耗竭来触发自身免疫(目标3)。我们将消除疲惫 标记物TIM-3来研究疲劳对自身免疫的贡献。我们将检查IL-2和微生物区系 反向控制Tfh糖酵解，调节T细胞耗竭。我们还将测试肠道来源的Tfh和TPH细胞 较少精疲力竭，并增加了人类类风湿关节炎的细胞血糖。总而言之，我们将学习如何 微生物区系通过改变肠道Tfh细胞的可塑性和耗竭而诱发肠道末端疾病。我们期待IL-2治疗 通过抑制Tfh细胞发挥作用，cTfh和TPH细胞可能作为一种非生物自身免疫信号发挥作用。这 该提案是独一无二的，因为它侧重于粘膜免疫及其与全身自身免疫的联系。 好了！

项目成果

The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis.

• DOI: 10.1186/s13075-017-1398-6
• 发表时间: 2017-08-15
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Teng F;Felix KM;Bradley CP;Naskar D;Ma H;Raslan WA;Wu HJ
• 通讯作者: Wu HJ

Synthetic Retinoid AM80 Ameliorates Lung and Arthritic Autoimmune Responses by Inhibiting T Follicular Helper and Th17 Cell Responses.

• DOI: 10.4049/jimmunol.1601776
• 发表时间: 2017-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Naskar D;Teng F;Felix KM;Bradley CP;Wu HJ
• 通讯作者: Wu HJ

Host-microbiota interplay in mediating immune disorders.

• DOI: 10.1111/nyas.13508
• 发表时间: 2018-04
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Felix KM;Tahsin S;Wu HJ
• 通讯作者: Wu HJ