Immune-mediated elimination of antigen-specific Tregs during infection and cancer

描述（由申请人提供）：Foxp 3+调节性T细胞（T细胞）是CD 4 T细胞的一个亚群，可抑制炎症反应，并作为自身免疫、癌症进展、同种异体移植排斥、母胎耐受和慢性感染的关键决定因素。肿瘤病变中高密度的TcB预示着许多人类肿瘤的临床结果较差，并且TcB限制了几种临床前癌症模型中的抗肿瘤反应。目前在临床环境中调节Treg介导的抑制的方法涉及整体耗竭或功能性消融，并且这些治疗与自身免疫的风险固有相关。因为Treg抑制功能需要通过抗原特异性T细胞受体（TCR）进行信号传导，所以在大多数疾病情况下主动限制免疫的那些TcR可能代表总TcR的一小部分，即对某些免疫系统特异的那些TcR。 表达的抗原。然而，尚未设计出选择性靶向这些抗原特异性T细胞的免疫策略。我们实验室在结核分枝杆菌（Mtb）感染小鼠模型中的工作表明，对Mtb衍生表位具有特异性的胸腺衍生的TbR群体在肺引流淋巴结中扩增，并在早期感染期间有效抑制发展中的适应性免疫应答。这种高度免疫抑制性Treg亚群不会持续存在，而是以IL-12 p40依赖性方式被宿主免疫应答选择性消除，而同一淋巴结中的其他Treg数量继续增加。利用我们和我们的合作者已经开发的实验系统来研究感染和癌症期间的抗原特异性T细胞，我们将对这一过程进行机械解剖。在目标1中，我们将鉴定驱动Mtb特异性Treg收缩的IL-12 p40依赖性细胞因子，并确定该细胞因子是否直接作用于Treg或通过其他细胞类型介导该效应。我们还将研究细胞因子通过诱导一氧化氮的产生介导Treg剔除的想法 物种在目标2中，我们将确定在何种程度上确定IL-12 p40依赖性途径调节前列腺抗原特异性T细胞在前列腺癌小鼠模型，并确定这些途径的实验操作是否可以诱导前列腺抗原特异性T细胞的特异性消除。这些研究将确定剔除病原体特异性Tcl 3所需的分子轴，并探索该途径对癌症背景下肿瘤相关Tcl 3的影响。这将为未来的研究开辟新的途径，并提出了一种独特的可能性，即该轴可以用于治疗，以选择性和安全地消除癌症和其他慢性疾病中有害的Treg亚群，其中抗原特异性Tlag限制免疫力。

DESCRIPTION (provided by applicant): Foxp3+ regulatory T cells (Tregs) are a subset of CD4 T cells that suppress inflammatory responses and serve as key determinants of autoimmunity, cancer progression, allograft rejection, maternal-fetal tolerance, and chronic infection. A high density of Tregs in tumor lesions predicts a poor clinical outcome in many human tumors, and Tregs restrict anti-tumor responses in several pre-clinical cancer models. Current approaches to modulating Treg-mediated suppression in the clinical setting involve global depletion or functional ablation, and these treatments are inherently associated with a risk of autoimmunity. Because Treg suppressive function requires signaling through the antigen-specific T cell receptor (TCR), those Tregs that are actively restricting immunity in most disease scenarios probably represent a small subset of the total Tregs, those that are specific for certain expressed antigens. However, immunotherapeutic strategies that selectively target these antigen-specific Tregs have not been devised. Work in our lab in the mouse model of Mycobacterium tuberculosis (Mtb) infection has revealed that a population of thymically-derived Tregs specific for a Mtb-derived epitope expands in the lung draining lymph node and potently suppresses the developing adaptive immune response during early infection. This highly immunosuppressive Treg subpopulation does not persist, but is selectively eliminated by the host immune response in an IL-12p40-dependent manner while other T regs in the same lymph node continue to increase in numbers. Utilizing the experimental systems that we and our collaborators have developed to study antigen-specific Tregs during infection and cancer, we will perform a mechanistic dissection of this process. In Aim 1, we will identify the IL-12p40-dependent cytokine that drives Mtb-specific Treg contraction and determine whether this cytokine acts directly on the Tregs or mediates the effect via other cell types. We will also investigate the idea that the cytokine mediates Treg culling by inducing production of nitric oxide species. In Aim 2, we will determine the extent to which the identified IL-12p40-dependent pathways regulate prostate antigen-specific T regs during a mouse model of prostrate cancer, and determine whether experimental manipulation of these pathways can induce the specific elimination of prostate antigen-specific T regs. These studies will identify a molecular axis that s required for the culling of pathogen- specific Tregs and explore the impact of this pathway on tumor-associated Tregs in the context of cancer. This will open new avenues for future investigation, and raises the distinct possibility that this axis could be exploited therapeuticall to selectively and safely eliminate harmful Treg subpopulations in cancer and other chronic diseases in which antigen-specific Tregs restrict immunity.