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

基本信息

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
项目类别：
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&apos 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

项目摘要

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。生态失调（肠道微生物群失衡）与肠道远端自身免疫有关疾病，如自身免疫性关节炎和狼疮。！然而，肠道微生物群影响的机制肠道远端/全身性疾病在很大程度上仍然未知。滤泡辅助 T (Tfh) 细胞专门帮助 B 细胞，过度的 Tfh 反应会使患者面临自身免疫的风险。以前，使用 K/BxN 自身免疫关节炎模型中，我们发现肠道共生分节丝状细菌（SFB）通过以下方式诱导关节炎驱动派尔氏淋巴结 (PP) Tfh 细胞分化并排出到全身部位，从而促进全身 Tfh 反应并加剧关节炎。 SFB 通过限制 IL-2 接触 CD4+ T 细胞来诱导 PP Tfh 分化，从而以树突状细胞 (DC) 依赖性方式增强 Tfh 细胞主调节因子 Bcl-6。尤其，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 CD25 的 DC，淬灭 T-B 细胞边界 CD4+ T 细胞分泌的 IL-2。我们将追踪肠道之间的单细胞迁移和全身部位，并识别循环 Tfh 细胞以及外周辅助 T (Tph) 细胞（一种新的细胞类型）在 RA 中发现的 B 细胞也有助于血液中的 B 细胞，作为我们体内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 自身免疫通过诱导表达双重 TCR 的 Th17 细胞。我们的新数据还表明，IL-17+ Tfh 样细胞的存在 SFB+ K/BxN 小鼠。我们假设微生物群促进 PP 中 Th17 转化为 Tfh 细胞，从而增强自身免疫性关节炎（目标 2）。我们将通过 Th17 命运图谱检查可塑性，并使用单一细胞 TCR 分析，以分析微生物群倾斜的双重 TCR 库是否会促进自身免疫。我们将使用 Cre-loxP 系统可解决 Th17 衍生的 Tfh 细胞的功能。慢性抗原 (Ag) 暴露原因 T 细胞耗竭。自身免疫T细胞也会遇到慢性Ag，但衰竭在自身免疫中的作用是不太清楚。长期暴露于 IL-2 会诱导 Blimp-1 并消耗细胞葡萄糖以促进 T 细胞 Bcl-6 可以对抗疲劳。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 细胞耗竭来触发自身免疫（目标 3）。我们将消除疲惫标记 Tim-3 用于研究疲劳对自身免疫的影响。我们将检查 IL-2 和微生物群是否反向控制 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 细胞是否在人类 RA 中，疲劳程度较低且细胞葡萄糖增加。总之，我们将学习如何微生物群通过改变肠道 Tfh 细胞的可塑性和耗竭来诱发肠道远端疾病。我们期待 IL-2 疗法通过抑制 Tfh 细胞发挥作用，cTfh 和 Tph 细胞可能充当失调的自身免疫信号。这该提案是独一无二的，因为它侧重于粘膜免疫及其与系统性自身免疫的联系。！