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

• 批准号: 10650735
• 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
• 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/10650735
• 关键词: Adopted; Adoptive Transfer; Agonist; Alleles; Amphiregulin; Area; Autoantigens; Bleomycin; Cell Therapy; Cell physiology; Cells; Cellular biology; Clinical; Computational Biology; Cues; Cytokine Receptors; Data; Detection; EGF gene; Family; Family member; Foundations; Gene Expression; Gene Expression Profile; Genes; Heterogeneity; Homeostasis; Human; IL18 gene; Immune; Immune Tolerance; Impairment; In Vitro; Infection; Inflammation; Influenza; Injury; Interleukin-1; 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 Induction; Signal Pathway; Signal Transduction; T cell response; T-Cell Proliferation; TLR7 gene; Testing; Therapeutic; Tissues; Treg therapy; Viral; Work; adaptive immunity; 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

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.

摘要 调节性T细胞(Treg)对维持免疫耐受至关重要，但最近它们的 在调节组织动态平衡的其他方面的重要性一直是人们非常感兴趣的领域。多数 与这一应用相关的是组织驻留树的种群，它们在受伤时积累并促进 通过产生EGF家族成员两性调节蛋白(ARG)等因子进行组织修复。这些修复功能 与传统上归因于Tregs的抑制功能不同，但指示Tregs 采用这些不同的功能模式尚未得到很好的定义。IL-1家族细胞因子IL-18和IL-33 在某种程度上，至少在某些组织中参与，但目前尚不清楚这些细胞因子是否起到 Treg函数的关键初始决定因素。 这一提议将检验这样一种假设，即Tregs中的Toll样受体7(TLR7)信号是 Treg组织修复功能。我们认为TLR7使Tregs能够感知病原体衍生的核酸作为 以及从受损的宿主组织中释放的自身RNA。我们的假设是基于我们对一组 TLR报告小鼠，这表明只有TLR7在Tregs上表达，以及强大的初步数据 证明TLR7可以诱导标志性组织修复基因ARIG在小鼠和小鼠体内的表达 人类树。使用新产生的具有Treg特异性TLR7缺失的小鼠，我们将检查 TLR7信号在Tregs肺损伤中的重要性(目标1)。单细胞RNA测序将识别 Tregs的哪些亚群由TLR7控制，并将定义Tregs中依赖TLR7的基因。我们会 使用Treg特异性缺失的小鼠，研究IL18R和IL33R信号在Treg中的重要性 并将决定TLR7、IL18R和IL33R在多大程度上调节不同方面的 Treg扩增和/或分化对不同肺损伤剂的反应(目标2)。最后，我们会 在我们最近工作的基础上，确定了TLR伴侣Unc93b1特异性地 抑制TLR7信号。使用带有突变的Unc93b1的小鼠的Tregs，这些突变的Unc93b1增强了TLR7信号， 我们将测试Tregs的过继治疗是否可以增强对病毒和自身RNA的TLR7反应 调解更有效的肺损伤修复(目标3)。 总之，这些研究将定义控制Treg组织修复功能的信号，并测试治疗 在肺损伤的情况下放大这些信号的可能性，这是迈向治疗的关键第一步 为了临床利益操纵Treg功能。