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: 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
• 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

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) 对于维持免疫耐受至关重要，但最近它们的 调节组织稳态其他方面的重要性一直是人们强烈关注的领域。最多 与该应用相关的是组织驻留调节性T细胞群，它们在损伤时积累并促进 通过产生 EGF 家族成员双调蛋白 (Areg) 等因子来修复组织。这些修复功能 与传统上认为 Tregs 的抑制功能不同，但指示 Tregs 的信号 采用这些不同的功能模式尚未得到明确定义。 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，但尚不清楚这些细胞因子是否充当 Treg 功能的关键初始决定因素。 该提案将检验 Tregs 中 Toll 样受体 7 (TLR7) 信号传导是关键决定因素的假设。 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 以及从受损宿主组织中释放的自身RNA。我们的假设是基于我们对一组数据的分析 TLR 报告小鼠，揭示 Tregs 上仅表达 TLR7，以及强有力的初步数据 证明 TLR7 可以在小鼠和小鼠体内诱导标志性组织修复基因 Areg 的表达 人类Tregs。使用新生成的 Treg 特异性删除 TLR7 的小鼠，我们将检查 TLR7 信号传导在肺损伤过程中 Tregs 中的重要性（目标 1）。单细胞 RNA 测序将鉴定 肺 Tregs 的哪些子集受 TLR7 控制，并将定义 Tregs 中 TLR7 依赖性基因。我们将 还使用具有 Treg 特异性缺失的小鼠研究 IL18R 和 IL33R 信号在 Tregs 中的重要性 这些受体的作用，并将决定 TLR7、IL18R 和 IL33R 调节不同方面的程度 针对不同肺损伤剂的 Treg 扩增和/或分化（目标 2）。最后，我们将 以我们最近的工作为基础，该工作确定了 TLR 伴侣 Unc93b1 专门通过该机制 抑制 TLR7 信号传导。使用具有增强 TLR7 信号传导的 Unc93b1 突变小鼠的 Tregs， 我们将测试对病毒和自身RNA具有增强的TLR7反应的Tregs的过继治疗是否可以 更有效地修复肺损伤（目标 3）。 总而言之，这些研究将定义控制 Treg 组织修复功能的信号并测试治疗效果 在肺损伤的情况下放大这些信号的潜力，这是治疗的关键第一步 操纵 Treg 功能以获得临床益处。