Control of Regulatory T Cell Function by Toll-Like Receptor 7

Toll 样受体 7 对调节性 T 细胞功能的控制

基本信息

批准号：
10304769
负责人：
Gregory M Barton
金额：
$ 56.43万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10304769
关键词：
Adopted Adoptive Transfer Agonist Alleles Amphiregulin Area Autoantigens Biology Bleomycin Cell Therapy Cell physiology Cells Clinical Computational Biology Cues Cytokine Receptors Data Detection EGF gene Family Family member Foundations Gene Expression Gene Expression Profile Genes Heterogeneity Homeostasis Human Immune Immune Tolerance Impairment In Vitro Infection Inflammation Influenza Injury Interleukin-1 Interleukin-18 Knockout Mice Ligands Link Lung Lung infections Maintenance Mediating Metabolism Modality Modeling Molecular Chaperones Mus Muscle Mutant Strains Mice Natural Immunity Nucleic Acids Population RNA Regulatory T-Lymphocyte Reporter Role Signal Pathway Signal Transduction TLR7 gene Testing Therapeutic Tissues Treg therapy Viral Work adaptive immunity base cytokine gene repair improved interest lung injury lung repair member mutant next generation sequencing pathogen receptor repair function repaired response sensor single-cell RNA sequencing therapeutic evaluation tissue repair viral RNA

项目摘要

ABSTRACT Regulatory T cells (Tregs) are critical for the maintenance of immunological tolerance but more recently their importance in regulating other aspects of tissue homeostasis has been an area of intense interest. Most relevant to this application are populations of tissue-resident Tregs that accumulate upon injury and facilitate tissue repair by producing factors such as the EGF family member amphiregulin (Areg). These repair functions are distinct from the suppressive function classically attributed to Tregs, but the signals that instruct Tregs to adopt these distinct functional modalities have not been well defined. The IL-1 family cytokines IL-18 and IL-33 are involved at some level, at least in certain tissues, but it remains unclear whether these cytokines act as the key initial determinants of Treg function. This proposal will test the hypothesis that Toll-like receptor 7 (TLR7) signaling in Tregs is a key determinant of Treg tissue repair function. We propose that TLR7 enables Tregs to sense pathogen-derived nucleic acids as well as self RNA released from damaged host tissues. Our hypothesis is based on our analysis of a panel of TLR reporter mice, which revealed that only TLR7 is expressed on Tregs, as well as strong preliminary data demonstrating that TLR7 can induce expression of the signature tissue repair gene, Areg, in both murine and human Tregs. Using newly generated mice with Treg-specific deletion of TLR7, we will examine the importance of TLR7 signaling in Tregs during lung damage (Aim 1). Single-cell RNA sequencing will identify which subsets of lung Tregs are controlled by TLR7 and will define TLR7-dependent genes in Tregs. We will also investigate the importance of IL18R and IL33R signaling in Tregs, using mice with Treg-specific deletion of these receptors, and will determine the extent to which TLR7, IL18R, and IL33R regulate distinct aspects of Treg expansion and/or differentiation in response to diverse lung damaging agents (Aim 2). Finally, we will build on our recent work that identified a mechanism by which the TLR chaperone Unc93b1 specifically dampens TLR7 signaling. Using Tregs from mice with mutant Unc93b1 that have enhanced TLR7 signaling, we will test whether adoptive therapy of Tregs with enhanced TLR7 responses to viral and self RNA can mediate more effective repair of lung damage (Aim 3). Altogether, these studies will define the signals that control Treg tissue repair functions and test the therapeutic potential of amplifying these signals in the context of lung damage, a key first step toward therapeutic manipulation of Treg function for clinical benefit.

抽象的调节性T细胞（TREG）对于维持免疫耐受性至关重要，但最近它们在调节组织稳态的其他方面的重要性一直是引起人们强烈关注的领域。最多与此应用有关通过产生诸如EGF家族成员两次凝胶蛋白（AREG）之类的因素修复组织。这些维修功能与经典归因于Treg的抑制功能不同，但是指示Tregs的信号采用这些独特的功能方式尚未得到很好的定义。 IL-1家族细胞因子IL-18和IL-33 至少在某些组织中涉及某种水平，但尚不清楚这些细胞因子是否起作用 treg功能的关键初始决定因素。该提案将检验以下假设：Tregs中的Toll样受体7（TLR7）信号是关键的决定因素 Treg组织修复功能。我们建议TLR7使Treg可以将病原体衍生的核酸视为以及从受损的宿主组织释放的自我RNA。我们的假设基于我们对一个小组的分析 TLR记者小鼠，揭示只有TLR7在Tregs上表达，并且强大的初步数据证明TLR7可以在鼠和人treg。使用与TLR7的Treg特异性缺失的新生成的小鼠，我们将检查肺损伤期间TRR7信号传导的重要性（AIM 1）。单细胞RNA测序将识别哪些肺Treg子集由TLR7控制，并将定义TREG中的TLR7依赖性基因。我们将还要研究使用具有Treg特异性缺失的小鼠在Tregs中IL18R和IL33R信号的重要性在这些受体中，将确定TLR7，IL18R和IL33R调节的不同方面的程度 Treg扩展和/或分化响应各种肺破坏药物（AIM 2）。最后，我们会的基于我们最近的工作，该工作确定了TLR伴侣UNC93B1的机制抑制TLR7信号传导。使用具有增强TLR7信号传导的突变体UNC93B1的小鼠的Tregs，我们将测试对TLR7对病毒和自我RNA的反应增强的Treg的过继疗法是否可以调解对肺损伤的更有效修复（AIM 3）。总之，这些研究将定义控制Treg组织修复功能并测试治疗的信号在肺损伤的背景下扩增这些信号的潜力，这是迈向治疗的关键第一步操纵Treg功能以获得临床益处。