T Regulatory cell responses in Toxoplasma-infected muscle

组织感染后，必须控制侵入的病原体，并对组织进行修复或 否则，长期的发病率和死亡率将随之而来。弓形虫感染导致 未解决的慢性感染，组织囊肿优先位于骨骼肌和 中枢神经系统。与大脑相比，人们对免疫反应知之甚少， 受感染肌肉中的免疫调节。表达Foxp3的CD4调节性T细胞(Tregs)发挥作用 在控制对感染的免疫反应和帮助组织修复方面发挥关键作用。然而，我们已经发现 在弓形虫的慢性感染过程中，肌肉寄生菌变得致病并引起炎症 防止它的发生。我们已经证明这些Treg是Th1极化的，但不产生干扰素γ。Tregs在T. 弓形虫感染的肌肉产生低水平的双调节蛋白，这是修复过程中的关键细胞因子 免疫介导的病理学。我们证明了弓形虫诱导的肌肉免疫病理学可以 在慢性感染的小鼠中通过重组双调蛋白治疗而得到改善 对组织起作用。然而，目前还不清楚两用调节素是如何调节这一效应的。最重要的是 这一理论的假设是，骨骼肌树突中T-bet的表达推动了这种致病 通过抑制与正常抑制的Treg功能相关的关键因子的产生来发挥作用。 这一假设将在以下具体目标中得到解决：(1)确定T-bet如何推动 Tregs在感染肌肉中的致病作用和(2)确定两亲调节蛋白在感染中的作用 在弓形虫感染过程中的肌肉。慢性感染如何改变高度精心策划的 免疫介导的肌肉再生仍然知之甚少。肌肉质量的丧失预示着 慢性疾病患者的生活质量降低，发病率往往增加，因此情况更好 为了指导治疗干预，需要了解是什么推动了这一过程。

After a tissue is infected, the invading pathogen must be controlled and the tissue must be repaired or else long-term morbidity and mortality will ensue. Toxoplasma gondii infections result in a non-resolving chronic infection with tissue cysts residing preferentially in skeletal muscle and the central nervous system. In contrast to the brain little is known about the immune response and immune-regulation in the infected muscle. Foxp3-expressing CD4+ regulatory T cells (Tregs) play a key role in controlling the immune response to infection and aid in tissue repair. Yet, we have found during chronic T. gondii infection muscle Tregs become pathogenic and cause inflammation instead of preventing it. We have shown these Tregs are Th1-polarized but do not produce IFNγ. Tregs in T. gondii-infected muscle produce low levels of amphiregulin, a cytokine critical in repairing immune-mediated pathology. We showed that Toxoplasma-induced immunopathology in muscle can be ameliorated by recombinant treatment with amphiregulin in chronically infected mice and returning function to the tissue. However it is unclear how amphiregulin mediates this effect. The overarching hypothesis for this proposal is that T-bet expression in skeletal muscle Tregs drives this pathogenic function by dampening production of key factors associated with normally suppressive Treg function. This hypothesis will be addressed in the following specific aims: (1) identify how T-bet drives the pathogenic function of Tregs in infected muscle and (2) define the role of amphiregulin in infected muscle during Toxoplasma infection. How a chronic infection alters the highly orchestrated immune-mediated regeneration of muscle is still poorly understood. Loss of muscle mass predicts reduced quality of life and often increased morbidity for chronically ill patients and so a better understanding of what drives this process is needed for directing therapeutic interventions.