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: 10532065
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532065
• 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; Cre lox recombination system; 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; antagonist; 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; microbiota; migration; mouse model; novel; pathobiont; potential biomarker; receptor; 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。营养不良（肠道微生物群体不平衡）与肠道自身免疫有关 疾病，例如自身免疫性关节炎和狼疮。然而，肠道菌群影响的机制 肠道/全身性疾病在很大程度上仍然未知。 T卵泡辅助器（TFH）细胞专门帮助B细胞， 过度的TFH反应使患者处于自身免疫性的危险中。以前，使用K/BXN自动免疫 关节炎模型，我们表明肠道分割的丝状细菌（SFB）通过 将Peyer斑块（PP）TFH细胞的分化和出现驱动到全身性位点，增强全身TFH 反应和加剧关节炎。 SFB通过限制IL-2访问CD4+ T细胞来诱导PP TFH分化， 因此，以树突状细胞（DC）依赖性方式增强BCl-6，TFH细胞主调节剂。尤其， 许多自身免疫性患者表现出IL-2缺乏症，而低剂量IL-2则提供了有希望的自身免疫治疗。 我们将确定微生物群介导的IL-2缺乏症如何影响与TFH相关的自身免疫性和IL-2 治疗（目标1）。我们将首先检查SFB的TFH细胞诱导是否依赖于表达CD25的DC， 在T-B细胞边界的CD4+ T细胞分泌的IL-2淬灭IL-2。我们将跟踪肠道之间的单细胞迁移 和全身位点并识别循环的TFH细胞以及外围辅助辅助剂T（TPH）细胞，一种新的细胞类型 在RA中发现的也有助于B细胞，作为血液的潜在生物标志物，可引起营养不良引起的自身免疫性。 小鼠模型和类风湿关节炎（RA）的患者。我们报道SFB促进K/BXN自动免疫性 通过诱导表达双重TCR的Th17细胞。我们的新数据还显示了IL-17+ TFH样细胞的存在 SFB+ K/BXN小鼠。我们假设微生物群促进了Th17转化为PPS中TFH细胞的转化， 增强了自身免疫性关节炎（AIM 2）。我们将通过Th17命运映射检查可塑性，并使用单个 细胞TCR分析以分析微生物群链的双TCR库是否促进自身免疫性。我们将使用 Cre-loxP系统以解决Th17衍生的TFH细胞的功能。慢性抗原（AG）暴露原因 T细胞耗尽。自身免疫性T细胞也遇到慢性AG，但疲惫在自身免疫性中的作用是 不太清楚。长时间的IL-2暴露会诱导Blimp-1并耗尽细胞葡萄糖以促进T细胞 精疲力尽，由BCL-6抵消。随着SFB降低IL-2信号传导并诱导BCL-6，我们将其化为 微生物群通过抑制T和/或TFH细胞耗尽来触发自身免疫性（AIM 3）。我们将消灭疲惫 标记TIM-3研究精疲力尽对自身免疫的贡献。我们将检查IL-2和微生物群是否 反向控制TFH糖酵解调节T细胞耗尽。我们还将测试肠道衍生的TFH和TPH细胞是否 在人RA中疲惫不堪，细胞葡萄糖的增加。总之，我们将学习如何 微生物群通过改变肠道TFH细胞的可塑性和疲惫来诱导肠道疾病。我们期望IL-2治疗 通过抑制TFH细胞的作用，并且CTFH和TPH细胞可以用作失调自身免疫性信号。这 提案是独一无二的，因为它专注于粘膜免疫及其与系统性自身免疫性的联系。 呢