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: 8495227
• 负责人: Matthias G. Von Herrath
• 金额: $ 43.73万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495227
• 关键词: Acute; Affect; Asthma; Autoimmune Diseases; Autoimmunity; Chronic; Collaborations; DNA Methylation; Data; Disease; Enhancers; 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; epigenetic marker; 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群体具有强烈和不同的影响。我们 初步数据表明，Foxp 3 + T细胞（适应性或天然存在的）和IL-10+ T细胞受到影响， 病毒感染。潜在的机制被认为与APC的调节有关， 特别是干扰素和TLR，导致对Treg激活、稳定性的强烈影响，这可能是 反映在Foxp 3启动子DNA甲基化状态的变化，以及细胞因子的产生， 基因组中表观遗传标记的整体模式的变化。明确定义基础 机制及其精确的效果不仅可以让我们更好地了解免疫系统的反应， 系统的病毒感染，但设计更好的策略，以诱导THBE治疗慢性 炎症性疾病如IBD、T1 D和哮喘。 目的1：急性或慢性病毒感染是否会使Foxp 3和/或IL-10表达和Treg活性在体外不稳定 还是在体内使用Foxp 3和IL-10基因报告小鼠，我们将检验我们的假设，即Foxp 3表达和IL-10基因的表达， IL-10的产生在病毒感染过程中受到调节，这取决于是否 感染是急性的（LCMV Armstrong）或慢性的（LCMV克隆13）。我们将比较 在病毒感染之前、期间和之后进行治疗。 目的2：THBE如何影响病毒感染、自身免疫和哮喘的结局？在这里我们将测试 我们的假设是，不同类型的Treg，尽管它们的功效，在结果方面是不可比的， 并在体内特定疾病情况下发挥作用。 目的3：病毒感染如何影响THBE的稳定性和功能机制？初步数据显示 Treg功能是通过APC而不是病毒感染对Treg的直接影响来影响的。此外 TLR 2似乎调节并最终扩增和激活Foxp 3 + TcR。我们建议玩家在 先天性免疫系统，如DC和TLR，沿着内源性配体，如热休克 热休克蛋白（HSPs）在决定结果中起着重要作用。