Microbiota Control Lung Th17 Cell Response and Plasticity Leading to Autoimmune Lung Disease

微生物群控制肺 Th17 细胞反应和可塑性导致自身免疫性肺病

• 批准号: 10447594
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 45.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447594
• 关键词: Address; Area; Arthritis; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; CCL20 gene; CCR6 gene; CD4 Positive T Lymphocytes; Cause of Death; Cell Communication; Cell Differentiation process; Cells; Cre lox recombination system; Data; Development; Disease; Dissection; Epithelial; Epithelial Cells; Equilibrium; Etiology; FOXP3 gene; Face; Fostering; Future; Glycolysis; Homing; Human; Hypoxia; Hypoxia Inducible Factor; In Situ; Industrialization; Interleukin-17; K/BxN model; Lesion; Ligands; Lung; Lung diseases; Measures; Mediating; Methods; Microbe; Microscopic; Modeling; Mus; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Pimonidazole; Population; Production; Prognosis; Public Health; Reporting; Rheumatoid Arthritis; Role; Signal Transduction; Site; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Tissues; alveolar epithelium; arthropathies; autoimmune arthritis; base; cell type; combat; commensal bacteria; design; dysbiosis; follow-up; gut bacteria; gut microbiota; gut-lung axis; hexokinase; inhibitor; lung microbiota; microbiota; migration; pathobiont; recruit; remote control; response; sensor; systemic autoimmune disease; tertiary lymphoid organ; tissue culture

Project Summary. Lung complications are a common and major cause of death in patients with rheumatoid arthritis (RA). Therapies are limited, and arthritis modulating drugs can actually worsen lung disease in RA patients, yet little is known regarding RA-related lung pathogenesis. It is evident that the gut and gut microbiota have a strong influence in many lung diseases. Mechanistically, this phenomenon known as the gut-lung axis, is poorly defined. We reported that through gut-lung communication, a gut commensal, segmented filamentous bacteria (SFB) are able to expand dual T cell receptor (TCR)-expressing T helper 17 (Th17) cells, leading to lung tertiary lymphoid structures (TLS), lesions often associated with poor prognosis in autoimmune patients. To understand gut-lung axis, we propose addressing the mechanisms utilized by SFB to promote a Th17 cell response, gut-lung migration, and lung TLS formation. Hypoxia-inducible factor-1α (HIF-1α) senses O2 in hypoxic tissues, e.g. the gut and inflamed tissues, and is known to enhance glycolysis and promote Th17 cell differentiation. Recent studies reported reoxygenation of T cells in tissue culture chambers greatly enhances HIF-1a induction. Importantly, gut (hypoxic)-derived T cells entering the lung (normoxic) may face similar O2 changes. We hypothesize and will test whether the gut microbiota in combination with lung reoxygenation up- regulate HIF-1α expression in gut-derived lung CD4+ T cells, promoting their glycolytic activity and Th17 cell commitment, and worsening lung disease. Using the KikGR-photoconvertible model to trace T cells from gut to lung, our new data favor our hypothesis by showing a higher HIF-1α level in KikR (gut-derived) than KikG CD4+ T cells in lung but not spleen of SFB+ mice. CCR6 is highly expressed by Th17 cells. Our new data show that type 2 alveolar epithelial cells (AEC2) produce abundant CCL20, the CCR6 ligand in the pre-autoimmune disease phase. We will test whether lung microbiota and innate signaling are required for AEC2s’ CCL20 expression and Th17 cell recruitment by using AEC2-specific MyD88 and CCL20 depletions. Recently, gut microbiota have been shown to locally induce an intriguing gut T cell type co-expressing Rorγt+ and Foxp3+, master regulators of Th17 cells and Tregs. However, whether and how gut microbiota can remotely regulate T cell plasticity in the lung remains unknown. Our new data show that a unique population of IL-17+Foxp3+ cells is significantly increased in lung of SFB+ over SFB− mice. We will examine T cell plasticity by Treg fate mapping, and use single cell TCR analysis to analyze whether a microbiota-skewed dual TCR repertoire allows Foxp3+ T cells to acquire a Th17-like phenotype. Finally, we will use the Cre-loxP system to address the “good or evil” function of IL-17+Foxp3+ T cells in lung autoimmunity. By taking a unique approach of tracking gut-lung crosstalk, this proposal permits studies to reveal the etiology of gut-lung axis, helping to pave the way for the designing of future therapies to combat gut-lung axis-related diseases.

项目总结。