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: 10090554
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 48.02万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090554
• 关键词: 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; Data; Dendritic Cells; Deoxyglucose; Development; Disease; Dissection; Distal; Dose; Epidemic; Exhibits; Exposure to; Functional disorder; Glucose; Glycolysis; Helper-Inducer T-Lymphocyte; Human; IL2RA gene; Immune; Immune System Diseases; Immunity; Immunoglobulin A; Immunologic Markers; Industrialization; Inflammatory; Interleukin-17; Interleukin-2; K/BxN model; Learning; Link; Lupus; Lymphoid Tissue; 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 Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Work; autoimmune arthritis; base; 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/antagonist; microbiota; migration; mouse model; novel; pathobiont; potential biomarker; receptor; recombinase-mediated cassette exchange; response; systemic autoimmune disease; systemic autoimmunity

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. !

项目摘要。肠道菌群失调（肠道微生物群失衡）与肠道远端自身免疫性疾病有关。 疾病，如自身免疫性关节炎和狼疮。然而，肠道微生物群影响 肠道远端/全身性疾病仍然在很大程度上未知。T滤泡辅助细胞（Tfh）专门帮助B细胞， 过度的Tfh反应使患者处于自身免疫的风险中。以前，使用K/BxN自身免疫 在关节炎模型中，我们发现肠道分节丝状菌（SFB）通过以下途径诱导关节炎： 驱动派伊尔集合淋巴结（PP）Tfh细胞分化和消退到全身部位， 反应和加剧关节炎。SFB通过限制IL-2进入CD 4 + T细胞诱导PP Tfh分化， 从而以树突状细胞（DC）依赖性方式增强Bcl-6（Tfh细胞主要调节物）。值得注意的是， 许多自身免疫患者表现出IL-2缺乏，低剂量IL-2提供了有希望的自身免疫治疗。 我们将确定微生物介导的IL-2缺乏如何影响Tfh相关的自身免疫和IL-2 治疗（目标1）。我们将首先检查SFB诱导Tfh细胞是否依赖于表达CD 25的DC， 淬灭由T-B细胞边界处的CD 4 + T细胞分泌的IL-2。我们将追踪单细胞在肠道 和全身部位，并确定循环Tfh细胞以及外周辅助性T（Tph）细胞，一种新的细胞类型 在RA中发现，它也有助于B细胞，在我们的研究中，它在血液中作为生态失调诱导的自身免疫的潜在生物标志物。 小鼠模型和类风湿性关节炎（RA）患者。我们报道了SFB促进K/BxN自身免疫 通过诱导双TCR表达Th 17细胞。我们的新数据还显示，在正常对照组中存在IL-17+ Tfh样细胞。 SFB+ K/BxN小鼠。我们假设微生物群促进PP中Th 17转化为Tfh细胞， 其增强自身免疫性关节炎（Aim 2）。我们将通过Th 17命运定位来检查可塑性，并使用单个 细胞TCR分析以分析微生物群偏斜的双TCR库是否促进自身免疫。我们将使用 Cre-loxP系统以解决Th 17衍生的Tfh细胞的功能。慢性抗原（Ag）暴露原因 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。长时间的IL-2暴露诱导Blimp-1并消耗细胞葡萄糖以促进T细胞增殖 衰竭，这是由Bcl-6对抗。由于SFB减少IL-2信号传导并诱导Bcl-6，我们推测， 微生物群通过抑制T和/或Tfh细胞耗竭触发自身免疫（目的3）。我们将消除疲劳 标记Tim-3来研究疲劳对自身免疫的贡献。我们将检测IL-2和微生物群 反向控制Tfh糖酵解以调节T细胞耗竭。我们还将测试肠道来源的Tfh和Tph细胞是否 在人RA中消耗较少并且具有增加的细胞葡萄糖。最后，我们将学习如何 微生物群通过改变肠道Tfh细胞可塑性和耗竭诱导肠道远端疾病。我们期待IL-2治疗 通过抑制Tfh细胞起作用，并且cTfh和Tph细胞可能充当生态失调的自身免疫信号。这 该提案是独特的，因为它侧重于粘膜免疫及其与系统性自身免疫的联系。 !