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. !

项目总结。生态失调（肠道菌群失衡）与肠道远端自身免疫有关