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.

项目总结/摘要 CD 8+抑制性T细胞在维持免疫稳态中起重要作用。但 这些细胞的表型和功能特征相对于它们的CD 4 调节性T细胞，即使有证据表明CD 8调节剂可能更重要， 比CD 4调节性T细胞更强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组织中，在小鼠中对抗其他健康组织 宽容且受监管的环境。一个关键的发现是组织中的炎症很快就被扑灭了 限制细胞对重要结构的损伤。在炎症过程的早期，免疫细胞从耐受的 库被募集到含有自身免疫性CTL的组织中。使用基因耗竭策略，我们 我了解到，在这种情况下，CD 8+调节因子比CD 4+调节因子对限制自身免疫性攻击更重要， 监管部门重要的是，在我们的模型中，可以通过过继转移CD 8+脾细胞来恢复调节。 其他未被操纵的动物该方法将IL 10和穿孔素确定为决定细胞凋亡的关键因素。 限制自身免疫攻击造成的损害的能力。然而，我们没有发现IL 10基因表达的证据， 使用IL-10报告基因的炎症组织中的CD 8“调节”细胞群表明IL-10可能起作用， 在这个过程的早期。此外，我们发现，固定调节性T细胞受体特异性， 人群并没有消除他们限制自身免疫攻击的能力。因此，我们开发了 总体假设，即IL 10对于CD 8+抑制细胞的产生是必需的， 抑制机制是通过穿孔素依赖性杀伤或灭活抗原特异性效应T细胞， 通过TcR独立识别过程介导的细胞。在这项研究中，我们试图获得所需的 关于IL 10在CD 8调节性T细胞的产生和功能中的作用的基本信息。我们 方法将是（1）鉴定与调节细胞相关的细胞表面表型标记，（2） 确定IL 10在这些CD 8调节性T细胞的产生和功能中的重要来源，以及（3）了解 这些调节细胞在何时何地形成沿着我们将研究替代的体外模型 为了能够有效地定义产生CD 8调节剂的分子机制，以及它们的能力， 限制激活CTL的功能。了解这种强大的免疫调节功能的基础， 提供关于如何增强或限制CTL攻击以有益于癌症或自身免疫性疾病的见解 患者。