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

描述(申请人提供)：Foxp3+调节性T细胞(Tregs)是CD4T细胞的一个亚群，它抑制炎症反应，是自身免疫、癌症进展、同种异体移植排斥、母婴耐受和慢性感染的关键决定因素。在许多人类肿瘤中，肿瘤病变中高密度的Tregs预示着不良的临床结果，并且在几个临床前癌症模型中，Tregs限制了抗肿瘤反应。目前在临床上调节Treg介导的抑制的方法包括整体耗竭或功能性消融，而这些治疗本身就与自身免疫的风险有关。因为Treg抑制功能需要通过抗原特异性T细胞受体(TCR)来传递信号，所以在大多数疾病情况下积极限制免疫的Treg可能只代表总Treg的一小部分，即某些特定的Treg 表达的抗原。然而，选择性地针对这些抗原特异性Treg的免疫治疗策略还没有被设计出来。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，针对Mtb衍生表位的胸腺衍生Tregs群体在肺引流淋巴结中扩张，并在感染早期有效地抑制发育中的适应性免疫反应。这种高度免疫抑制的Treg亚群不会持续存在，但会被宿主免疫反应以IL-12p40依赖的方式选择性地消除，而同一淋巴结中的其他T regs数量继续增加。利用我们和我们的合作者开发的实验系统来研究感染和癌症期间的抗原特异性Tregs，我们将对这一过程进行机械剖析。在目标1中，我们将确定驱动Mtb特异性Treg收缩的IL-12p40依赖的细胞因子，并确定该细胞因子是直接作用于Treg还是通过其他细胞类型介导这一效应。我们还将研究细胞因子通过诱导一氧化氮的产生来介导Treg剔除的想法 物种。在目标2中，我们将确定已识别的IL-12p40依赖的通路在多大程度上调节前列腺癌小鼠模型中前列腺抗原特异的T调节器，并确定这些通路的实验操作是否可以诱导前列腺抗原特异性T调节器的特异性消除。这些研究将确定S在剔除病原体特异性Treg所需的分子轴，并探索这一途径在癌症背景下对肿瘤相关Treg的影响。这将为未来的研究开辟新的途径，并增加了这一轴被用于治疗ALL的明显可能性，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，在这些疾病中，抗原特异性Treg会限制免疫。

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.