Regulatory T cells dictate immunity during persistent Salmonella infection

描述（由申请方提供）：伤寒是一种由宿主适应性沙门氏菌引起的持续性感染。奇怪的是，当免疫介导的损害超过感染造成的直接风险时，允许病原体持续存在也可能对宿主有益。我们的长期目标是确定沙门氏菌感染期间激活的免疫细胞和信号，其控制病原体根除所需的免疫激活与免疫介导的宿主损伤的相关风险之间的平衡，以及以病原体持久性为代价的免疫抑制。S.鼠伤寒感染再现了人类伤寒持续感染的重要特征。再加上大量的免疫学工具和试剂仅在小鼠中可用，该物种中的感染是目前用于识别控制这种微妙的免疫平衡的分子和细胞信号的最佳可用模型。使用这个模型，我们的初步研究表明，调节性T细胞（Tcells），包括一个独特的谱系的CD4+ T细胞的特征是Foxp3表达在决定免疫激活和细菌持久性之间的平衡发挥关键作用。感染后早期，Foxp3+ Treg消融加速细菌根除的动力学，而增加Foxp3+ Treg导致病原体负荷的相互增加。因此，本申请的总体目标是定义相对重要性，并确定在持续性沙门氏菌感染过程中TdR所利用的抑制机制。目的1将扩展我们的初步发现，证明在早期（第5天）和晚期（第37天）时间点分离的细胞的Treg抑制效力的急剧变化，通过定义持续感染期间Treg抑制效力变化的综合动力学分析。我们的具体目标是确定Treg抑制效力何时达到峰值、最低点和返回基线水平，以及这些变化的绝对幅度。这些结果将建立补充实验的框架，这些实验通过量化Treg消融的相对影响来验证Treg在这些关键时间点的重要性。使用最近开发的用于用来自在确定的Treg相关分子中具有靶向缺陷的小鼠的供体Treg重建Treg消融的小鼠的技术，目的2将进一步探索Treg抑制效力的这些变化的机制基础。这些实验包括鉴定和分离控制宿主防御的特定Treg相关分子与维持外周免疫耐受所需的分子，并定义沙门氏菌配体和相应的模式识别受体，这些受体通过细胞内在刺激决定Treg抑制效力的变化。这些利用尖端免疫学工具的实验不仅填补了我们目前对Foxp3+ Tclase在沙门氏菌感染期间控制宿主防御的重要性和机制的认识的重要空白，而且还为Tclase如何在其他持续感染期间调节免疫力建立了重要的范例。

DESCRIPTION (provided by applicant): Typhoid fever is a persistent infection caused by host adapted Salmonella species. Paradoxically, allowing pathogen persistence may also be beneficial for the host when immune-mediated damage outweigh the immediate risk posed by the infection. Our long-term goals are to identify the immune cells and signals activated during Salmonella infection that controls this balance between immune activation required for pathogen eradication with the associated risk of immune-mediated host injury, and immune suppression at the expense of pathogen persistence. The mouse model of S. typhimurium infection reproduces important features of persistent infection characteristic of human typhoid. Together with the abundance of immunological tools and reagents available only in mice, infection in this species is currently the best-available model for identifying the molecular and cellular signals that control this delicate immunological balance. Using this model, our preliminary studies indicate regulatory T cells (Tregs) that comprise a distinct lineage of CD4+ T cells characterized by Foxp3-expression play critical roles in dictating the balance between immune activation and bacterial persistence. Early after infection, Foxp3+Treg-ablation accelerates the kinetics of bacterial eradication, while augmenting Foxp3+Tregs causes reciprocal increases in pathogen burden. Therefore the overall goals of this application are to define the relative importance and identify the suppressive mechanism utilized by Tregs throughout persistent Salmonella infection. Aim 1 will expand on our preliminary findings that demonstrate drastic changes in Treg suppressive potency for cells isolated at early (day 5) and late (day 37) time points, by defining a comprehensive kinetic analysis for changes in Treg suppressive potency during persistent infection. Our specific goals are to identify when Treg suppressive potency peaks, nadirs, and returns to baseline levels, and the absolute magnitude for these changes. These results will establish the frame-work for complementary experiments that verify the importance of Tregs at these critical time points by quantifying the relative impacts of Treg-ablation. Using recently developed techniques for reconstituting Treg- ablated mice with donor Tregs from mice with targeted defects in defined Treg-associated molecules, Aim 2 will further explore the mechanistic basis for these changes in Treg suppression potency. These include experiments that will identify and dissociate the specific Treg-associated molecules that control host defense from those required for sustaining peripheral immune tolerance, and define Salmonella ligands and the corresponding pattern recognition receptors that dictate these changes in Treg suppression potency through cell-intrinsic stimulation. Together these experiments that utilize cutting edge immunological tools will not only fill important gaps in our current knowledge on the importance and the mechanism whereby Foxp3+Tregs control host defense during Salmonella infection, but also establish important paradigms for how Tregs may regulate immunity during other persistent infections.