Control of regulatory T cell homeostasis and function by Notch signaling

通过 Notch 信号传导控制调节性 T 细胞稳态和功能

• 批准号: 9913447
• 负责人: Talal Amine Chatila
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-04 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913447
• 关键词: Allergic; Allergic inflammation; Asthma; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Cell Compartmentation; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chronic; Disease; Ensure; FOXP3 gene; Functional disorder; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immunity; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Lead; Ligands; Mediating; Mus; Mutation; NOTCH3 gene; Nature; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Peripheral; Physiological; Play; Proteins; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Specificity; Systemic Lupus Erythematosus; T-Lymphocyte; Th1 Cells; Th2 Cells; Therapeutic; Transcriptional Activation; Transcriptional Regulation; allergic airway inflammation; cytokine; functional outcomes; graft vs host disease; in vivo; loss of function; loss of function mutation; notch protein; novel; novel therapeutics; programs; protein function; receptor; response; restoration; transcriptome

Abstract Foxp3+ regulatory T (TR) play a requisite role in peripheral immunological tolerance and in restraining exuberant immune responses. Elucidating mechanisms that control TR cell responses is of pivotal importance to the restoration of tolerance in diseases of chronic inflammation and autoimmunity. Relevant to this goal is our recent determination of a critical role for the Notch pathway in regulating the peripheral TR cell compartment. TR cell-specific deletion of Notch1 antagonized T helper (Th)1 responses and protected against graft versus host disease, while TR cell-specific constitutive expression of the intracellular domain of Notch1 led to lymphoproliferation, Th1 cell dysregulation and autoimmunity. We have also demonstrated that TR cell- specific loss of function Notch pathway mutations that incapacitate signaling via all Notch receptors (Pofut1 deletion) or canonical pathway signaling (Rbpj deletion) but not deletion of Notch1 or Notch2, protected against allergic airway inflammation, indicating that individual Notch receptors on TR cells mediated regulation of distinct Th cell programs. Some of the effects of Notch signaling in TR cells involved transcriptional activation via the canonical Notch pathway co-factor RBPJ. Yet others appeared to involve activation of the non- canonical mechanisms. Accordingly, We hypothesize that Notch signaling fulfills an important physiological role in negatively regulating TR cells to ensure optimal immune homeostasis. Excessive activation of this pathway would result in TR cell dysfunction, leading to immune dysregulation, inflammation and autoimmunity. We further hypothesize that individual Notch receptors on TR cells fulfill non-redundant roles in controlling Th cell responses, with Notch1 regulating Th1 and Notch4 Th2 cell responses, respectively. We also hypothesize that the capacity of individual Notch receptors on TR cells to mediate distinct immune regulatory outcomes is reflected by hierarchal Notch receptor-ligand interactions and by distinct transcriptional circuitries activated by the respective Notch receptors. We propose under Aim 1 to elucidate mechanisms by which sustained Notch1 signaling in TR cells promotes dysregulated Th1 cell responses by enabling complete Th1 cell reprogramming of TR cells, and the role of T follicular regulatory (TFR) cell subversion by Notch1 signaling in inciting intense humoral autoimmunity. Under Aim 2, we will examine mechanisms by which Notch signaling in TR cells, most notably that by Notch4 (and possibly Notch3), regulates Th2 cell responses in allergic airway inflammation, while Aim 3 will explore mechanisms by which signaling via different Notch receptors in TR cells leads to distinct functional outcomes, including ligand specificity of the respective receptor expressed on TR cells and the nature of the downstream transcriptional programs activated upon Notch1 versus Notch4 signaling. The proposed studies will identify novel mechanisms by which Notch signaling controls TR cell activities relevant to different inflammatory paradigms, and will have bearing on common immune dysregulatory diseases, including autoimmune disorders, graft versus host disease and allergic inflammation such as in asthma.

摘要 Foxp 3+调节性T（TR）在外周免疫耐受中起着必要的作用， 旺盛的免疫反应阐明控制TR细胞反应的机制至关重要 恢复慢性炎症和自身免疫性疾病的耐受性。与这一目标相关的是 我们最近确定了Notch通路在调节外周TR细胞中的关键作用， 车厢TR细胞特异性Notch 1缺失拮抗辅助性T细胞（Th）1应答，并保护 移植物抗宿主病，而TR细胞特异性组成型表达Notch 1的细胞内结构域 导致淋巴细胞增生、Th 1细胞失调和自身免疫。我们还证明了TR细胞- 特异性功能丧失Notch途径突变，其使通过所有Notch受体（Pofut 1）的信号传导丧失能力 缺失）或经典途径信号传导（Rbpj缺失），但不缺失Notch 1或Notch 2， 过敏性气道炎症，表明TR细胞上的单个Notch受体介导了 不同的Th细胞程序。Notch信号在TR细胞中的一些作用涉及转录激活 通过经典Notch途径辅因子RBPJ。然而，其他人似乎涉及激活非- 规范机制因此，我们假设Notch信号传导实现了一个重要的生理学功能。 在负调节TR细胞以确保最佳免疫稳态中的作用。过度激活这个 在某些情况下，TR通路可能导致TR细胞功能障碍，导致免疫失调、炎症和自身免疫。 我们进一步假设TR细胞上的单个Notch受体在控制Th 细胞应答，Notch 1分别调节Th 1和Notch 4 Th 2细胞应答。我们还假设 TR细胞上单个Notch受体介导不同免疫调节结果的能力， 反映在分级Notch受体-配体相互作用和不同的转录电路激活， 各自的Notch受体在目标1下，我们提出阐明维持Notch 1的机制， TR细胞中的信号传导通过使完整的Th 1细胞重编程而促进失调的Th 1细胞应答 以及Notch 1信号转导对T滤泡调节细胞（TFR）的颠覆作用， 体液性自身免疫在目标2下，我们将研究TR细胞中Notch信号传导的机制， 值得注意的是，通过Notch 4（可能还有Notch 3），调节过敏性气道炎症中的Th 2细胞应答， 而Aim 3将探索通过TR细胞中不同Notch受体的信号传导导致 不同的功能结果，包括TR细胞上表达的相应受体的配体特异性， Notch 1与Notch 4信号传导激活的下游转录程序的性质。的 提出的研究将确定Notch信号转导控制TR细胞活动的新机制， 不同的炎症范例，并将与常见的免疫失调疾病，包括 自身免疫性疾病、移植物抗宿主病和过敏性炎症如哮喘。