Functions of Hopx in immune tolerance in a model of Multiple Sclerosis

Hopx 在多发性硬化症模型免疫耐受中的作用

• 批准号: 8767156
• 负责人: Daniel Hawiger
• 金额: $ 37.67万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767156
• 关键词: Acute; Area; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD44 gene; Cell physiology; Cells; Dendritic Cells; Disease; Encephalomyelitis; FOS gene; Foundations; Generations; Genes; Genetic Transcription; Goals; IL2RA gene; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunotherapy; Inflammatory; Interleukin-2; Investigation; JUN gene; Link; Lymphocyte; Mediating; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Pathway interactions; Peripheral; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Serum Response Factor; Signal Transduction; T-Lymphocyte; anergy; autoreactive T cell; homeodomain; mouse model; novel; public health relevance; research study

DESCRIPTION (provided by applicant): A breakdown of immune tolerance and the generation of pro-inflammatory lymphocytes cause autoimmune diseases, including Multiple Sclerosis (MS). Dendritic cells (DCs) induce immunity and tolerance and therefore represent a promising target for new immune-therapies of MS. Pathways of T cell tolerance that include deletion, anergy, and immune-suppression of autoreactive T cells were shown to confer protection from disease in autoimmune Experimental Acute Encephalomyelitis (EAE), a mouse model of MS. However, the specific mechanisms of tolerance mediated by DCs remain unclear. We recently discovered that Homeodomain Only Protein (Hopx) directs Treg cell-mediated immune unresponsiveness induced by DCs. Hopx is a transcription co-factor that differently regulates expression of c- jun/c-fos and other genes through its interactions with other proteins including Serum Response Factor (SRF). Our most recent findings reveal that DCs mediate tolerance through intimately linked pathways involving the early induction of tolerance in T cells that become unresponsive to activation in EAE, induce expression of Hopx and Hopx+/Foxp3neg cells can convert into Hopx+/Foxp3+ peripheral (p)Treg cells. These extrathymically- induced pTreg cells then mediate long-lasting tolerance to block autoimmune EAE. Hopx expressed in pTreg cells maintains the functions of these regulatory cells by inhibiting their expression of IL-2. Our results firmly establish Hopx as the first characterized transcription co-factor specifically required for DC- induced tolerance to avert autoimmunity, and they open a new area of investigation in immune tolerance mediated by DCs. Our long-term goals are to establish a novel and comprehensive model of Hopx functions in tolerance. We will reveal molecular pathways of Hopx in pTreg cells by clarifying functions of specific Hopx molecular targets including IL-2 in Aim 1. We will discern regulation of Hopx expression in tolerance in Aim 2. We will define the role for Hopx in diverse mechanisms of tolerance mediated by various types of DCs in Aim 3. The results of the proposed experiments may become a foundation of more selective and efficient therapies for MS as well as other types of autoimmune diseases.

描述（由申请人提供）：免疫耐受的破坏和促炎性淋巴细胞的产生会导致自身免疫性疾病，包括多发性硬化症（MS）。树突状细胞（DC）可诱导免疫和耐受，因此是多发性硬化症新免疫疗法的一个有希望的靶点。 T细胞耐受途径，包括自身反应性T细胞的缺失、无反应性和免疫抑制，在自身免疫性实验性急性脑脊髓炎（EAE）（一种多发性硬化症小鼠模型）中被证明可以预防疾病。然而，DC介导的耐受的具体机制仍不清楚。我们最近发现仅同源域蛋白 (Hopx) 可以指导 DC 诱导的 Treg 细胞介导的免疫无反应。 Hopx 是一种转录辅助因子，通过与血清反应因子 (SRF) 等其他蛋白质的相互作用，以不同方式调节 c-jun/c-fos 和其他基因的表达。我们最新的研究结果表明，DC 通过密切相关的途径介导耐受性，这些途径涉及 T 细胞的早期诱导耐受性，这些 T 细胞对 EAE 中的激活无反应，诱导 Hopx 的表达，并且 Hopx+/Foxp3neg 细胞可以转化为 Hopx+/Foxp3+ 外周 (p)Treg 细胞。然后，这些胸腺外诱导的 pTreg 细胞会介导持久的耐受性，以阻止自身免疫性 EAE。 pTreg 细胞中表达的 Hopx 通过抑制 IL-2 的表达来维持这些调节细胞的功能。我们的 结果牢固地确立了 Hopx 是 DC 诱导的耐受以避免自身免疫所需的第一个特征转录辅助因子，并且它们开辟了 DC 介导的免疫耐受的新研究领域。我们的长期目标是建立一种新颖且全面的 Hopx 耐受功能模型。我们将通过阐明特定 Hopx 分子靶标（包括目标 1 中的 IL-2）的功能来揭示 pTreg 细胞中 Hopx 的分子途径。我们将在目标 2 中辨别 Hopx 表达在耐受性中的调节。我们将在目标 3 中定义 Hopx 在各种类型的 DC 介导的多种耐受机制中的作用。所提出的实验结果可能成为针对 MS 以及其他疾病更具选择性和更有效的治疗的基础。 自身免疫性疾病的类型。