Treg stability in viral infection and autoimmunity

我们的假设是，病毒感染对不同的Treg人群有强烈而不同的影响。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 被病毒感染。潜在的机制被认为与APC的调制有关，在 特定的干扰素和TLRs，导致对Treg的激活、稳定产生强烈影响，这可能是 反映在Foxp3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。清楚地定义潜在的 机制及其准确的影响将使我们不仅能够更好地了解免疫系统的反应 病毒感染的系统，但设计更好的策略来诱导Tregs用于治疗慢性 炎症性疾病，如IBD、T1D和哮喘。 目的1：急性或慢性病毒感染是否在体外破坏Foxp3和/或IL-10的表达和Treg活性 还是在活体内？使用Foxp3和IL-10基因报告小鼠，我们将检验我们的假设Foxp3表达和 IL-10的产生在病毒感染过程中受到调节，而这一过程的发生取决于 感染是急性的(LCMV阿姆斯特朗)或慢性的(LCMV克隆13)。我们将比较的效应器函数 病毒感染之前、期间和之后的特雷格。 目标2：Treg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，不同的Treg类型，尽管它们的疗效不同，但在结果方面是不可比的 并在体内特定的疾病情况下发挥作用。 目标3：病毒感染是如何影响Tregs的稳定性和功能的？初步数据显示 Treg的功能是通过APC影响的，而不是病毒感染对Treg的直接影响。此外 TLR2似乎调节并最终扩张和激活Foxp3+Tregs。我们建议参赛选手 先天免疫系统，如DC和TLR，以及内源性配体，如热休克 蛋白质(HSPs)在决定结果中起着重要作用。

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.