IL-10/IL10R in the Regulation of Self-Reactive CTL by CD8+ T-cells

IL-10/IL10R 在 CD8 T 细胞调节自身反应性 CTL 中的作用

• 批准号: 9223809
• 负责人: LARRY R PEASE
• 金额: $ 23.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-06 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223809
• 关键词: Acute; Address; Adoptive Transfer; Animals; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Characteristics; Chickens; Complex; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Effector Cell; Elements; Environment; Equilibrium; Experimental Models; Family Picornaviridae; Future; Gene Expression; Generations; Genetic; Goals; Homeostasis; IL10 gene; IL2 gene; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunosuppression; Inflammation; Inflammatory; Informal Social Control; Insulin; Interferon Type II; Interleukin-10; Investigation; Knowledge; Learning; Maintenance; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Memory; Modeling; Molecular; Mus; OVA-8; Ovalbumin; Pancreas; Pancreatic Injury; Patients; Phenotype; Play; Population; Process; Production; Protocols documentation; Rattus; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Reporter; Reporting; Resolution; Role; Scheme; Source; Spleen; Structure; Suppressor-Effector T-Lymphocytes; Surface; System; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenes; Vaccination; Virus; Work; autoreactivity; base; cell growth; cellular targeting; cytokine; cytotoxicity; immune system function; immunoregulation; in vitro Model; in vivo; insight; killings; perforin; phenotypic biomarker; promoter; receptor; response; vector-induced

PROJECT SUMMARY/ABSTRACT CD8+ suppressor T-cells play important roles in the maintenance of immune homeostasis. However, the phenotypic and functional characteristics of these cells remains poorly characterized relative to their CD4 regulatory T cell counterparts, even though some evidence suggests CD8 regulators can be more important than CD4 T regulatory cells. We have been investigating the cellular determinants limiting autoimmune attack in mice against otherwise healthy tissue by introducing and activating self-reactive T cells into a normally tolerant and regulated environment. A key finding is that inflammation in the tissue is quickly extinguished limiting cellular damage to vital structures. Early in the inflammatory process immune cells from the tolerant repertoire are recruited into the tissues harboring autoimmune CTL. Using genetic depletion strategies, we learned that CD8+ regulators are more critical to limiting autoimmune attack in this setting than are CD4+ regulators. Importantly, regulation can be restored in our model by adoptive transfer of CD8+ spleen cells from otherwise unmanipulated animals. This approach identified IL10 and perforin as critical factors determining the ability to limit the damage by autoimmune attack. However, we failed to find evidence of IL10 gene expression the CD8 “regulatory” cell population in inflamed tissue using an IL10 reporter suggesting that IL10 may act earlier in the process. Furthermore, we found that fixing the T cell receptor specificity of the regulatory population did not ablate their ability to limit autoimmune attack. Accordingly, we have developed the overarching hypothesis that IL10 is essential for the generation of CD8+ suppressor cells and that the mechanism of suppression is through a perforin-dependent killing or inactivation of antigen specific effector T- cells mediated through a TcR independent recognition process. In this study, we seek to acquire needed fundamental information about the role IL10 in the generation and function of CD8 regulatory T cells. Our approach will be to (1) identify the cellular surface phenotypic markers associated with the regulatory cells, (2) identify important sources of IL10 in the generation and function of these CD8 regulatory T cells, and (3) learn where and when these regulatory cells are formed. Along the way we will examine alternative in vitro models to enable efficient definition of the molecular mechanisms giving rise to CD8 regulators and to their ability to limit the functions of activated CTL. Understanding the basis of this strong immune regulatory function could provide insights into how to augment or limit CTL attack for the benefit of cancer or autoimmune disease patients, respectively.

项目摘要/摘要 CD8+抑制性T细胞在维持免疫稳态中起着重要作用。然而， 这些细胞的表型和功能特征与它们的CD4相比仍然很差 调节性T细胞对应物，尽管一些证据表明CD8调节器可能更重要 而不是CD4T调节细胞。我们一直在研究限制自身免疫攻击的细胞决定因素。 通过将自身反应性T细胞引入并激活正常的 宽容和规范的环境。一个关键的发现是，组织中的炎症很快就会消失 将细胞损伤限制在重要结构上。在炎症过程的早期，免疫细胞从耐受 谱系被招募到含有自身免疫性CTL的组织中。使用基因枯竭策略，我们 了解到在这种情况下，CD8+调节器在限制自身免疫攻击方面比CD4+更关键 监管者。重要的是，在我们的模型中，通过过继转移CD8+脾细胞可以恢复调节 否则就是不受操控的动物。这种方法确定IL-10和穿孔素是决定 能够限制自身免疫攻击造成的伤害。然而，我们未能找到IL10基因表达的证据 炎症组织中CD8“调节”细胞群使用IL10记者暗示IL10可能起作用 在这个过程的早些时候。此外，我们还发现，固定T细胞受体的调节性 人群并没有削弱他们限制自身免疫攻击的能力。因此，我们开发了 最重要的假设是，IL10对于CD8+抑制细胞的产生是必不可少的，并且 抑制的机制是通过穿孔素依赖的杀伤或灭活抗原特异性效应器T- 细胞通过TCR非依赖的识别过程介导。在这项研究中，我们寻求获得所需的 关于IL10在CD8调节性T细胞的产生和功能中的作用的基本信息。我们的 方法将是(1)识别与调节细胞相关的细胞表面表型标记，(2) 确定在这些CD8调节性T细胞的产生和功能中IL10的重要来源，以及(3)了解 这些调控细胞在何时何地形成。在此过程中，我们将研究替代的体外模型 为了能够有效地定义产生CD8调节器的分子机制及其能力 限制激活的CTL的功能。了解这种强大的免疫调节功能的基础可能会 提供有关如何增强或限制CTL攻击以利于癌症或自身免疫性疾病的见解 分别为患者。