Injury-Specific Activation of the Immune System

免疫系统损伤特异性激活

• 批准号: 8115690
• 负责人: JAMES A. LEDERER
• 金额: $ 41.45万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115690
• 关键词: Address; Adoptive Transfer; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autoimmune Responses; Behavior; Burn injury; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cell Lineage; Cell surface; Cells; Clinical; Data; Dependence; Environment; Flow Cytometry; Genes; Histocompatibility Antigens Class II; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Injury; Knock-in Mouse; MHC Class II Genes; Measures; Mediating; Molecular; Mus; Nature; Operative Surgical Procedures; Opportunistic Infections; Ovalbumin; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Role; Series; Shock; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Specificity; T-Cell Receptor; T-Lymphocyte; TNFSF5 gene; Testing; Tissues; Transgenic Mice; Trauma; Work; ZAP-70 Gene; antimicrobial; clinically significant; immune function; injured; innovation; lymph nodes; man; memory recall; prevent; receptor; receptor binding; research study; response; response to injury

DESCRIPTION (provided by applicant): The inflammatory and counter-inflammatory behavior of the immune system following severe injury governs the clinical trajectory of critically-injured patients. For example, a dominant counter- inflammatory phenotype will suppress normal anti-microbial immunity and predispose the host to opportunistic infections. On the other hand, augmentation of inflammation can promote systemic inflammatory shock if infectious complications occur in injured patients. We have reported that a distinct subset of CD4 T cells called regulatory T cells (Tregs) are activated by injury and act to potently suppress both T cell mediated immune function and injury-induced inflammation. Thus, we suggest that Tregs act as an injury-reactive cell subset with the capacity to control both innate and adaptive immune function. The experiments in this project will test this hypothesis and will uncover the cellular and molecular pathways responsible for the rapid activation of Tregs by injury. The following specific aims are proposed: 1. to determine if Tregs are activated by injury by antigen receptor dependent or independent mechanisms. CD4 T cells are specifically activated by T cell receptor (TCR) binding to antigens presented by cell-surface MHC class II (MHCII) molecules on antigen presenting cells. The experiments in this aim will address the MHCII-dependence on Treg activation using MHCII gene deficient (MHCII-/-) mice, FoxP3-GFP gene knock-in mice, and adoptive transfer approaches. Innate (MyD88 and TRIF) and T cell costimulatory pathways (CD40L, CD28, and CTLA-4) will also be tested as potential MHCII independent pathways for the injury-specific activation of Tregs. 2. To characterize injury-specific activation and signaling by Tregs. The early activation of Tregs by burn injury suggests that Tregs respond rapidly and specifically to injury. In this aim, we propose to identify and study TCR-dependent and TCR-independent signaling pathways that are activated in Tregs by burn injury in mice. The experiments in this aim will use phospho-flow cytometry to measure MHCII-, TLR-, CD28-, CD40L-, or CTLA4-dependent activation of Tregs. 3. To define the specificity and nature of injury-specific recall responses by Tregs. The recent discovery that Tregs display a recall memory-like response to burn injury supports the idea that Tregs may respond specifically to injury. Studies in this aim will further investigate this basic finding and will use this observation to advance our understanding of injury-specific immune responses. The clinical significance of this project is that this information could be used to develop innovative approaches for controlling the immune system complications that occur in critically-injured trauma and surgical patients. PUBLIC HEALTH RELEVANCE: The behavior of the immune system following severe injury governs the clinical course of critically-injured patients. We have reported that a distinct subset of CD4 T cells called regulatory T cells (Tregs) are activated by injury and that Tregs can potently suppress immune system responses following injury in mice and man. The focus of this project will be to identify the initiating cellular and molecular pathways responsible for Treg activation by injury to generate basic information for developing innovative approaches for controlling immune system complications in critically-injured trauma and surgical patients.

描述（由申请人提供）：严重损伤后免疫系统的炎症和抗炎行为决定了重伤患者的临床轨迹。例如，显性的抗炎表型会抑制正常的抗微生物免疫力，并使宿主容易受到机会性感染。另一方面，如果受伤患者出现感染性并发症，炎症的加剧会促进全身炎症休克。我们报道了 CD4 T 细胞的一个独特子集，称为调节性 T 细胞 (Treg)，在损伤时会被激活，并有效抑制 T 细胞介导的免疫功能和损伤引起的炎症。因此，我们认为 Tregs 作为损伤反应细胞亚群，具有控制先天性和适应性免疫功能的能力。该项目中的实验将检验这一假设，并揭示导致 Treg 因损伤而快速激活的细胞和分子途径。提出以下具体目标： 1.确定Tregs是否通过抗原受体依赖性或独立机制因损伤而被激活。 CD4 T 细胞通过与抗原呈递细胞上的细胞表面 MHC II 类 (MHCII) 分子呈递的抗原结合的 T 细胞受体 (TCR) 特异性激活。该目的的实验将使用 MHCII 基因缺陷 (MHCII-/-) 小鼠、FoxP3-GFP 基因敲入小鼠和过继转移方法来解决 MHCII 对 Treg 激活的依赖性。先天（MyD88 和 TRIF）和 T 细胞共刺激通路（CD40L、CD28 和 CTLA-4）也将作为潜在的 MHCII 独立通路进行测试，用于 Treg 的损伤特异性激活。 2. 表征Tregs 的损伤特异性激活和信号传导。烧伤导致的 Tregs 早期激活表明 Tregs 对损伤做出快速且特异性的反应。为此，我们建议鉴定和研究 TCR 依赖性和 TCR 独立信号通路，这些通路在小鼠烧伤损伤的 Tregs 中被激活。该实验将使用磷酸流式细胞术来测量 MHCII、TLR、CD28、CD40L 或 CTLA4 依赖性 Tregs 激活。 3. 定义 Tregs 的损伤特异性回忆反应的特异性和性质。最近发现 Tregs 对烧伤表现出类似回忆的反应，这支持了 Tregs 可能对损伤做出特异性反应的观点。这一目标的研究将进一步调查这一基本发现，并将利用这一观察结果来增进我们对损伤特异性免疫反应的理解。该项目的临床意义在于，这些信息可用于开发控制重伤创伤和手术患者中发生的免疫系统并发症的创新方法。 公共卫生相关性：严重损伤后免疫系统的行为决定着重伤患者的临床病程。我们报道了 CD4 T 细胞的一个独特子集，称为调节性 T 细胞 (Treg)，在损伤时会被激活，并且在小鼠和人类损伤后，Treg 可以有效抑制免疫系统反应。该项目的重点是确定损伤导致 Treg 激活的起始细胞和分子途径，以生成基本信息，用于开发控制重伤创伤和手术患者免疫系统并发症的创新方法。