Role of Tim-1 and Bregs in Tolerance and Autoimmunity

Tim-1 和 Bregs 在耐受性和自身免疫中的作用

• 批准号: 10214479
• 负责人: VIJAY K. KUCHROO
• 金额: $ 49.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214479
• 关键词: Address; Affect; Age; Animals; Apoptotic; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Process; Cell Surface Receptors; Cell surface; Cells; Collaborations; Data; Data Set; Defect; Development; Human; Immune; Immune Tolerance; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; LoxP-flanked allele; Mediating; Modeling; Mucin 1 protein; Mus; Organ; Population; Process; Production; Protocols documentation; Regulatory T-Lymphocyte; Role; Self Tolerance; Severities; Signal Transduction; Tissues; base; cell type; conditional knockout; differential expression; humoral immunity deficiency; loss of function; macrophage; mutant; novel therapeutic intervention; phosphatidylserine receptor; reconstitution; response; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY Accumulating evidence supports that regulatory B cells (Bregs), are essential for limiting inflammation and autoimmunity by IL-10-dependent and -independent manners. The lack of a universal marker for identifying Bregs, however, has hampered our understanding of their critical biologic functions. The processes and mechanisms by which Bregs are generated have also not been identified. Dr. Rothstein’s lab as well as our own have shown that Tim-1 identifies IL-10-producing Bregs. We have generated a mouse with loss of function Tim-1 mutant (Tim-1∆mucin), and found that both Tim-1∆mucin and traditional Tim-1 deficient (Tim-1-/-) show progressive loss of IL-10 production in B cells. Additionally, with age, these mice developed severe multi-organ tissue inflammation. We have recently demonstrated that Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. B cells from both mice are unable to produce IL-10 in response to AC. Thus, we hypothesis that Tim-1 is also critical and essential for optimal Breg function in maintaining immune tolerance and limiting inflammatory responses by sensing AC, which will be addressed in Aim 1 by using Tim-1 floxed mice we recently generated. In addition to producing IL-10, our RNA-seq analysis have demonstrated that Tim-1+ Bregs also express many other inhibitory molecules, some of which have been shown to regulate IL-10-independent Breg function. We have also demonstrated that some inhibitory molecules regulate IL-10 in Tim-1+ Bregs. Therefore, we hypothesize that Tim-1+ Bregs exert their regulatory function not only by producing IL-10, but also by expressing a panel of inhibitory molecules, which give Bregs the optimal ability to suppress autoimmune responses—this will be examined in Aim 2. Our RNA- seq dataset identified a set of transcription factors differentially expressed in Tim-1+ Bregs. Thus, we propose to study the role of the transcription factors in Bregs in Aim 3. These studies will greatly increase our understanding of the role of Tim-1 in Bregs and the role of Bregs in immune tolerance and autoimmunity, and may also provide a novel therapeutic strategy by targeting B cells for the treatment of autoimmune diseases. !

项目概要 越来越多的证据支持调节性 B 细胞 (Breg) 对于限制炎症和 通过IL-10依赖性和非依赖性方式产生自身免疫。缺乏通用的识别标记 然而，布雷格阻碍了我们对其关键生物学功能的理解。流程和 Breg 的产生机制也尚未确定。 Rothstein 博士的实验室以及我们的 自己的研究表明，Tim-1 可以识别产生 IL-10 的 Bregs。我们已经生成了一只丧失功能的小鼠 Tim-1 突变体（Tim-1Δmucin），发现 Tim-1Δmucin 和传统 Tim-1 缺陷型（Tim-1-/-）均表现出 B 细胞中 IL-10 的产生逐渐丧失。此外，随着年龄的增长，这些小鼠出现了严重的多器官损伤 组织炎症。我们最近证明 Bregs 上的 Tim-1 是凋亡细胞 (AC) 所必需的 与 Bregs 结合并用于 AC 诱导 Bregs 中 IL-10 的产生。两只小鼠的 B 细胞均无法产生 IL-10 对 AC 的反应。因此，我们假设 Tim-1 对于最佳 Breg 函数也是至关重要的 通过感测 AC 来维持免疫耐受和限制炎症反应，这将得到解决 在目标 1 中，使用我们最近生成的 Tim-1 floxed 小鼠。除了产生 IL-10 之外，我们的 RNA-seq 分析表明 Tim-1+ Bregs 还表达许多其他抑制分子，其中一些 已被证明可以调节不依赖于 IL-10 的 Breg 功能。我们还证明了一些 抑制分子调节 Tim-1+ Bregs 中的 IL-10。因此，我们假设 Tim-1+ Bregs 发挥其作用 调节功能不仅通过产生 IL-10，还通过表达一组抑制分子， 赋予 Bregs 抑制自身免疫反应的最佳能力——这将在目标 2 中进行检查。我们的 RNA- seq 数据集鉴定了一组在 Tim-1+ Bregs 中差异表达的转录因子。因此，我们建议 研究目标 3 中 Bregs 转录因子的作用。这些研究将大大提高我们的 了解 Tim-1 在 Bregs 中的作用以及 Bregs 在免疫耐受和自身免疫中的作用，以及 还可能通过靶向 B 细胞来治疗自身免疫性疾病提供一种新的治疗策略。 ！