Treg stability in viral infection and autoimmunity

病毒感染和自身免疫中 Treg 的稳定性

• 批准号: 8377922
• 负责人: Matthias G. Von Herrath
• 金额: $ 46.53万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377922
• 关键词: Acute; Affect; Asthma; Autoimmune Diseases; Autoimmunity; Chronic; Collaborations; DNA Methylation; Data; Disease; Enhancers; Epigenetic Process; Genome; Heat shock proteins; Human; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response Pathway; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-10; Ligands; Lymphocytic choriomeningitis virus; Maintenance; Methylation; Mus; Nature; Outcome; Pattern; Play; Population; Production; Publishing; Regulatory T-Lymphocyte; Reporter Genes; Role; TLR2 gene; Testing; Virus; Virus Diseases; cytokine; in vitro activity; in vivo; promoter; response

Our hypothesis is that viral infections have strong and diverging effects on different Treg populations. Our preliminary data indicate that Foxp3+ Tregs (adaptive or naturally occurring) and IL-10+ Tregs are affected by viral infections. The underlying mechanisms are proposed to be related to the modulation of APCs, in particular interferons and TLRs, resulting in strong effects on Treg activation, stability, which could be reflected in changes in the DNA methylation status ofthe Foxp3 promoter, and cytokine production, reflected in changes in the overall pattern of epigenetic markers in the genome. Clearly defining the underlying mechanisms and their precise effects will allow us not only to better understand the response of the immune system to viral infections, but to devise better strategies to induce Tregs for the treatment of chronic inflammatory disorders such as IBD, T1D and asthma. Aim 1: Do acute or chronic viral infections destabilize Foxp3 and/or IL-10 expression and Treg activity in vitro or in vivo? Using Foxp3 and IL-10 gene reporter mice, we will test our hypothesis that Foxp3 expression and IL-10 production are modulated during viral infection, and that this occurs differentially depending on whether the infection is acute (LCMV Armstrong) or chronic (LCMV Clone 13). We will compare effector functions of Tregs before, during, and after viral infections. Aim 2: How do Tregs influence the outcome of viral infections, autoimmunity, and asthma? Here we will test our hypothesis that different Treg types, in spite of their efficacy, are not comparable in terms of outcome and function in particular disease situations in vivo. Aim 3: How do viral infections affect Tregs stability and function mechanistically? Preliminary data indicate that Treg function is affected via APCs rather than a direct influence of viral infections on Tregs. In addition TLR2 appears to modulate and eventually expand and invigorate Foxp3+ Tregs. We propose that players in the innate immune system,such as DCs and TLRs, along with endogenous ligands, such as heat shock proteins (HSPs), play an important role in determining the outcome.

我们的假设是，病毒感染对不同的 Treg 群体具有强烈且不同的影响。我们的 初步数据表明 Foxp3+ Tregs（适应性或自然发生）和 IL-10+ Tregs 受到影响 通过病毒感染。潜在的机制被认为与 APC 的调制有关， 特定的干扰素和 TLR，对 Treg 激活、稳定性产生强烈影响，这可能是 反映在 Foxp3 启动子的 DNA 甲基化状态和细胞因子产生的变化，反映 基因组中表观遗传标记总体模式的变化。明确定义底层 机制及其精确效果将使我们不仅能够更好地了解免疫反应 病毒感染系统，但设计更好的策略来诱导Tregs来治疗慢性疾病 炎症性疾病，如 IBD、T1D 和哮喘。 目标 1：急性或慢性病毒感染是否会破坏 Foxp3 和/或 IL-10 表达以及体外 Treg 活性的稳定性 还是体内？使用 Foxp3 和 IL-10 基因报告小鼠，我们将检验我们的假设，即 Foxp3 表达和 IL-10 的产生在病毒感染期间受到调节，并且这种情况的发生有所不同，具体取决于是否 感染为急性（LCMV 阿姆斯特朗）或慢性（LCMV 克隆 13）。我们将比较效应器功能 病毒感染之前、期间和之后的 Tregs。 目标 2：Tregs 如何影响病毒感染、自身免疫和哮喘的结果？这里我们将测试 我们的假设是，不同的 Treg 类型尽管具有功效，但在结果方面没有可比性 并在体内特定疾病情况下发挥作用。 目标 3：病毒感染如何影响 Tregs 的稳定性和功能？初步数据表明 Treg 功能是通过 APC 影响的，而不是病毒感染对 Treg 的直接影响。此外 TLR2 似乎可以调节并最终扩展并激活 Foxp3+ Tregs。我们建议玩家在 先天免疫系统，例如 DC 和 TLR，以及内源性配体，例如热休克 蛋白质（HSP）在决定结果方面发挥着重要作用。