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: 9040746
• 负责人: Andrew P. Fontenot
• 金额: $ 43.88万
• 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/9040746
• 关键词: Adoptive Transfer; Alleles; Antigens; Automobile Driving; Beryllium; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Cells; Chronic berylliosis; Complex; Data; Development; Disease; Environment; Epitopes; Exhibits; 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; Positioning Attribute; Proliferating; Proteins; 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 immunity; base; cytokine; human disease; human subject; inhibitor/antagonist; migration; mouse model; novel; peptide A; plexin; public health relevance; research study; stem; trafficking; 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(申请人提供)：慢性铍病(CBD)是一种由工作场所Be暴露引起的肺部肉芽肿性疾病，其特征是Be特异性的、分泌Th1型细胞因子的CD4+T细胞在肺内积聚。遗传易感性与β链第69位含有谷氨酸的人类白细胞抗原-DP等位基因密切相关 (CD4Glu69)，大多数β+T细胞以HLADP限制性方式识别。我们已经开发了一种人类白细胞抗原-DP2转基因(TG)小鼠的CBD模型，它复制了许多在人类疾病中看到的发现。Be氧化物(BeO)暴露的HL A-DP2 TG小鼠在支气管血管周围分布有单核细胞浸润，主要由效应和调节性CD4+T细胞组成。BE反应、人类白细胞抗原DP2限制性的CD4+T细胞存在于暴露于BeO的人类白细胞抗原DP2转基因小鼠中，但在野生型小鼠中不存在。在Beo暴露的HL A-DP2 TG小鼠中，Treg细胞的耗尽加剧了肺部炎症并促进了肉芽肿的形成，这表明Treg细胞抑制了BE特异性效应分子CD4T细胞和肉芽肿炎症。此外，我们最近发现了BE依赖的模拟表位和自体多肽，包括那些源自丛状蛋白A的多肽，它们可以刺激来自CBD患者肺部的BE特异性CD4+T细胞。用Be负载的HLADP2-Plexin A4四聚体，在所有表达HLADP2的αβ患者和大多数暴露于BEO的HLADP2Tg小鼠的支气管肺泡灌洗液中都发现了该CD4TCR特异性T细胞。此外，在慢性阻塞性肺疾病患者和BeO暴露小鼠的肺中，HLA-DP2-Plexin A4/BE四聚体染色的CD4+T细胞亚群表达FoxP3，表明诱导了表位特异性Treg细胞。推动抗原特异性效应T细胞和Treg细胞在BeO暴露的HL A-DP2 TG小鼠肺中招募和/或扩展的因素，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发展，构成了当前提议的基础。因此，我们假设暴露于BE可以诱导BE特异性效应细胞CD4T细胞和Treg细胞之间的动态相互作用，并且这些不同的抗原特异性T细胞亚群的扩张调节了BE的免疫反应。利用逆转录TCR HLA-DP2TG小鼠，第一个特定目的将确定BE特异性CD4+T细胞在BE诱导的肉芽肿性炎症发生中的致病性，而第二个目标将评估Treg细胞在BE特异性肉芽肿免疫反应产生中的作用。在第三个特定目标中，我们将把我们的研究结果从HLA-DP2转基因小鼠移植到患有CBD的人类受试者身上。与任何其他人类肺部疾病不同，我们的建议的新颖性源于我们能够以抗原特异性的方式研究小鼠和人类肺部适应性免疫反应的发展，并分析针对同一抗原复合体的效应器和Treg细胞之间的相互作用。总之，这些研究将加强我们对CBD免疫发病机制的理解，并有可能导致替代免疫抑制剂的治疗方案。