Interactions between antigen-specific effector and regulatory T cells in beryllium-induced disease

铍诱发疾病中抗原特异性效应细胞和调节性 T 细胞之间的相互作用

• 批准号: 9198986
• 负责人: Andrew P. Fontenot
• 金额: $ 42.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198986
• 关键词: Adoptive Transfer; Alleles; Antigens; Automobile Driving; Beryllium; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic berylliosis; Complex; Data; Development; Disease; Environment; Epitopes; Exhibits; FOXP3 gene; Frequencies; Generations; Genetic Predisposition to Disease; Glutamic Acid; Granuloma; Granulomatous; HLA-DP Antigens; HLA-DP2; Human; Hypersensitivity; IL2RA gene; Immune response; Immunosuppressive Agents; Inflammation; Lead; Ligands; Link; Lung; Lung Inflammation; Lung diseases; Mononuclear; Mus; Occupational; Oxides; Pathogenicity; Patients; Peptides; Peripheral; Positioning Attribute; Proliferating; Proteins; Recruitment Activity; Regimen; Regulatory T-Lymphocyte; Role; Severity of illness; Specimen; Staining method; Stains; System; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Therapeutic; Transgenic Mice; Translating; Wild Type Mouse; Workplace; adaptive immune response; cytokine; experimental study; human disease; human subject; inhibitor/antagonist; migration; mouse model; novel; peptide I; plexin; public health relevance; stem; translational study

 DESCRIPTION (provided by applicant): Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by be exposure in the workplace and is characterized by the accumulation of Be-specific, Th1-type cytokine-secreting CD4+ T cells in the lung. Genetic susceptibility is strongly linked to HLA-DP alleles that contain a glutamic acid at the 69th position of the β-chain (βGlu69), and the majority of CD4+ T cells recognize is in an HLA-DP-restricted manner. We have developed an HLA-DP2 transgenic (Tg) mouse model of CBD that replicates many of the findings seen in the human disease. Be oxide (BeO)-exposed HLA-DP2 Tg mice develop mononuclear infiltrates in a peribronchovascular distribution that are predominantly composed of effector and regulatory CD4+ T cells. Be-responsive, HLA-DP2- restricted CD4+ T cells are present in BeO-exposed HLA-DP2 Tg mice but not in wild-type mice. Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbates lung inflammation and enhances granuloma formation, suggesting that Treg cells inhibit Be-specific effector CD4 T cells and granulomatous inflammation. In addition, + we have recently identified Be-dependent mimotopes and self-peptides, including those derived from plexin A proteins, that stimulate Be-specific CD4+ T cells derived from the lungs of CBD patients. Using Be-loaded HLA- DP2-plexin A4 tetramers, CD4+ T cells specific for this αβTCR ligand have been identified in the bronchoalveolar lavage (BAL) fluid of all HLA-DP2-expressing CBD patients and the majority of BeO-exposed HLA-DP2 Tg mice. Furthermore, a subset of HLA-DP2-plexin A4/Be tetramer-staining CD4+ T cells in the lung of CBD patients and BeO-exposed mice express FoxP3, indicating the induction of epitope-specific Treg cells. The factors driving the recruitment and/or expansion of antigen-specific effector T cells and Treg cells in the lungs of BeO-exposed HLA- DP2 Tg mice, the interplay between these T cell subsets and how they modulate granuloma development form the basis of the current proposal. Thus, we hypothesize that Be exposure induces a dynamic interplay between Be-specific effector CD4 T cells and Treg cells and that the expansion of these distinct antigen-specific T cell subsets modulates the immune response to Be. Using retrogenic TCR HLA-DP2 Tg mice, the first specific aim will determine the pathogenicity of Be-specific CD4+ T cells in the generation of Be-induced granulomatous inflammation while the second aim will assess the role of Treg cells in the generation of a Be-specific granulomatous immune response. In the third specific aim, we will translate our findings from HLA-DP2 Tg mice to human subjects with CBD. Unlike any other human lung disease, the novelty of our proposal stems from our ability to study the development of an adaptive immune response in the lungs of mice and humans in an antigen- specific manner and analyze the interaction between effector and Treg cells specific for the same antigenic complex. Together, these studies will strengthen our understanding of immunopathogenesis of CBD and potentially lead to therapeutic alternatives to immunosuppressive agents.

 描述（由申请人提供）：慢性铍病（CBD）是一种由工作场所接触铍引起的肉芽肿性肺部疾病，其特征是Be特异性、Th1型细胞因子分泌CD4+T细胞在肺部积聚。易感性与 β 链第 69 位含有谷氨酸的 HLA-DP 等位基因密切相关 (βGlu69)，并且大多数 CD4+ T 细胞以 HLA-DP 限制的方式识别。我们开发了 CBD 的 HLA-DP2 转基因 (Tg) 小鼠模型，它复制了人类疾病 Be 中的许多发现。氧化铍 (BeO) 暴露的 HLA-DP2 Tg 小鼠在支气管血管周围分布中出现单核浸润，主要由效应细胞和调节性 CD4+ T 细胞组成。 Be 反应性 HLA-DP2-CD4+ T 细胞存在于 BeO 暴露的 HLA-DP2 Tg 小鼠中，但不存在于野生型小鼠中 BeO 暴露的 HLA-DP2 受限 Tg 小鼠中 Treg 细胞的耗尽会加剧肺部炎症并增强。肉芽肿形成，表明 Treg 细胞抑制 Be 特异性效应 CD4 T 细胞和肉芽肿炎症。此外，我们最近还鉴定了 Be 依赖性模拟表位和。自身肽，包括源自丛蛋白 A 蛋白的肽，可刺激来自 CBD 患者肺部的 Be 特异性 CD4+ T 细胞。在所有表达 HLA-DP2 的 CBD 患者和大多数暴露于 BeO 的 HLA-DP2 Tg 小鼠的支气管肺泡灌洗 (BAL) 液中发现了这种病毒。 CBD 患者和 BeO 暴露小鼠肺部的 HLA-DP2-plexin A4/Be 四聚体染色 CD4+ T 细胞亚群表达 FoxP3，表明表位特异性 Treg 细胞的诱导是驱动招募和/或扩增的因素。 BeO 暴露的 HLA-DP2 Tg 小鼠肺中抗原特异性效应 T 细胞和 Treg 细胞的变化，这些 T 细胞亚群之间的相互作用以及它们如何调节肉芽肿的形成因此，我们认为 Be 暴露会诱导 Be 特异性效应 CD4 T 细胞和 Treg 细胞之间的动态相互作用，并且这些不同抗原特异性 T 细胞亚群的扩展可调节对 Be 的免疫反应。逆转录 TCR HLA-DP2 Tg 小鼠，第一个具体目标将确定 Be 特异性 CD4+ T 细胞在 Be 诱导的肉芽肿性炎症生成中的致病性，而第二个目标将评估 Treg 细胞在生成在第三个具体目标中，我们将把 HLA-DP2 Tg 小鼠的发现转化为患有 CBD 的人类受试者，与任何其他人类肺部疾病不同，我们提案的新颖性源于我们研究的能力。以抗原特异性方式在小鼠和人类的肺部产生适应性免疫反应，并分析对同一抗原复合物具有特异性的效应细胞和 Treg 细胞之间的相互作用，这些研究将加强我们对 CBD 免疫发病机制的理解，并可能引领未来。治疗替代方案至免疫抑制剂。