Defining the Role of Regulatory T Cells in Resolution of Acute Lung Injury

定义调节性 T 细胞在解决急性肺损伤中的作用

• 批准号: 10532739
• 负责人: Jason Robert Mock
• 金额: $ 58.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532739
• 关键词: Acceleration; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Autoantigens; Autoimmunity; Cell Cycle Kinetics; Cell Proliferation; Cell Separation; Cell physiology; Cells; Coculture Techniques; Code; Complement; Disease; Epithelial Cells; Epithelium; Experimental Models; FOXP3 gene; Fibrin; Gene Expression; Genes; Genetic Transcription; Histone Deacetylase; Histones; Homing; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Injury; Knowledge; Light; Liquid substance; Lung; Lung diseases; Lysine; MME gene; Mediating; Morbidity - disease rate; Mus; Patients; Peripheral; Phase; Play; Pneumonia; Process; Proliferating; Protein-Serine-Threonine Kinases; Proteolysis; Publishing; Recovery; Regulatory T-Lymphocyte; Resolution; Role; Sentinel; Serine; Severities; Signal Transduction; Streptococcus pneumoniae; Structure of parenchyma of lung; T cell response; T cell therapy; T-Lymphocyte; Technology; Testing; Thymus Gland; Tissues; Transcript; Type II Epithelial Receptor Cell; Untranslated RNA; adaptive immunity; alveolar epithelium; cytokine; demethylation; immune cell infiltrate; improved; improved outcome; in vitro testing; lung injury; lung repair; mortality; novel; pathogen; repaired; reparative process; response; response to injury; restraint; therapeutic development; therapy outcome; transcriptome; transcriptomic profiling

Project Summary There is a paucity of information known about how the lung recovers from acute respiratory distress syndrome (ARDS) and pneumonia, and this knowledge gap has contributed to the continued high morbidity and mortality of these diseases. A subset of immune cells, Foxp3+ regulatory T lymphocytes (Tregs), is thought to be important in resolution in several experimental models of acute lung injury (ALI). Furthermore, Tregs are present in the lung of patients with ARDS, suggesting that they contribute to ARDS recovery. Tregs can arise from either thymic or extra-thymic origins. Extra-thymic, peripherally-induced Tregs (iTregs) are converted from naïve T cells and serve distinct and essential functions in controlling adaptive immunity to restrain immune cell infiltrates in the bronchial and bronchiolar walls. Furthermore, our published studies show that during the resolving phase of lung injury, Tregs expand in number and change their gene expression profiles compared to Tregs in uninjured control lungs. Treg transcriptome profiling identifies several genes that shine a light on novel functions of Tregs during ALI resolution. One transcript that is markedly upregulated 23-fold in Tregs isolated from resolving lung tissue is matrix metalloproteinase 12 (Mmp12). Importantly, mice lacking endogenous Tregs and repleted with Mmp12-/- Tregs by adoptive transfer have elevated inflammatory cells and less epithelial proliferation during resolution than mice repleted with Mmp12+/+ Tregs. The Treg transcriptome also suggests that downregulated expression of Treg transcripts Kdm6b and Sik1, both of which act to regulate gene transcription, may function to regulate Treg homing, retention, stability, and survival. The Aims seek to test the central hypothesis that Tregs are critical to resolution and that by optimizing Treg responses, ALI severity can be reduced, and resolution hastened. Aim 1 investigates the role of iTregs during resolution of ALI resolution. The hypothesis is that iTregs are required for optimal resolution of inflammation and lung repair after ALI induced by LPS, S. pneumoniae, and influenza A. The direct effects of Tregs and iTregs will be determined using in vitro co-cultures of Tregs and AT2 cells. Aim 2 determines the impact of Treg-expressed MMP12 during the resolution of ALI. The hypothesis is that Treg expression of MMP12 exerts multiple roles in orchestrating and facilitating the resolution of ALI. Substrates of Treg MMP12 will be identified in BAL fluid and lung tissue. Aim 3 determines if the differentially regulated transcripts, Kdm6b and Sik1, regulate Treg-promoted resolution of ALI. We will test the hypothesis that Tregs deficient in Kdm6b have decreased Foxp3 expression levels and delayed, inadequate resolution and that Tregs deficient in Sik1 have improved quality of resolution. We anticipate that the proposed studies will determine the roles iTregs play in ALI resolution and identify mechanisms by which Tregs mediate resolution and repair. Identifying and elucidating these mechanisms will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the beneficial response to injury.

项目概要 关于肺部如何从急性呼吸窘迫综合征中恢复的信息很少 （ARDS）和肺炎，这种知识差距导致了持续的高发病率和死亡率 免疫细胞的一个子集 Foxp3+ 调节性 T 淋巴细胞 (Treg) 被认为在这些疾病中发挥着重要作用。 在急性肺损伤 (ALI) 的几个实验模型中得到解决 此外，Tregs 存在于 ARDS 患者的肺部，表明它们有助于 ARDS 的恢复。 或胸腺外起源，外周诱导的 Tregs (iTregs) 由幼稚 T 细胞转化而来。 在控制适应性免疫以抑制免疫细胞浸润方面发挥独特和重要的作用 此外，我们发表的研究表明，在肺的消退阶段。 与未受伤对照中的 Tregs 相比，损伤后 Tregs 的数量增加并改变了其基因表达谱 Treg 转录组分析鉴定了几个基因，这些基因揭示了 Tregs 的新功能。 ALI 解析。从解析肺组织中分离出的 Tregs 中显着上调 23 倍的转录本是 重要的是，小鼠缺乏内源性 Tregs，但充满了 Mmp12-/-。 过继转移的 Treg 在消退过程中炎症细胞增多，上皮增殖减少 与充满 Mmp12+/+ Tregs 的小鼠相比，Treg 转录组也表明表达下调。 Treg 转录本 Kdm6b 和 Sik1 均具有调节基因转录的作用，可能具有调节 Treg 归巢、保留、稳定性和生存旨在检验 Treg 至关重要的中心假设。 通过优化 Treg 反应，可以降低 ALI 的严重程度，并加速解决目标。 图 1 研究了 iTreg 在 ALI 消退过程中的作用 假设 iTreg 是 ALI 消退所必需的。 LPS、肺炎链球菌和甲型流感引起的 ALI 后炎症和肺部修复的最佳解决。 Tregs 和 iTreg 的直接作用将通过 Tregs 和 AT2 细胞 Aim 的体外共培养来确定。 图 2 确定 Treg 表达的 MMP12 在 ALI 缓解过程中的影响 假设是 Treg。 MMP12 的表达在协调和促进 ALI 底物的解决中发挥多种作用。 将在 BAL 液和肺组织中鉴定 Treg MMP12，目的 3 确定是否存在差异调节。 转录本 Kdm6b 和 Sik1 调节 Treg 促进的 ALI 缓解 我们将检验 Tregs 的假设。 Kdm6b 缺陷导致 Foxp3 表达水平降低，分辨率延迟、分辨率不足，并且 Tregs Sik1 的缺陷提高了分辨率的质量，我们预计拟议的研究将确定 iTregs 在 ALI 解决中发挥的作用并确定 Tregs 介导解决和修复的机制。 识别和阐明这些机制将有助于开发治疗方法，以最大限度地减少 附带的组织损伤，而不会对损伤的有益反应产生不利影响。