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: 10455068
• 负责人: VIJAY K. KUCHROO
• 金额: $ 49.22万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455068
• 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. !

项目摘要 越来越多的证据支持调节性B细胞（BCRs）对于限制炎症和 IL-10依赖性和非依赖性的自身免疫。缺乏一个通用的标记来识别 然而，细菌阻碍了我们对其关键生物功能的理解。的过程和 也没有确定产生细菌的机制。罗斯坦博士的实验室和我们的 我们已经证明Tim-1识别产生IL-10的BclB。我们制造了一只功能丧失的老鼠 Tim-1突变体（Tim-1 β粘蛋白），并发现Tim-1 β粘蛋白和传统Tim-1缺陷型（Tim-1-/-）都显示出 B细胞中IL-10产生的进行性丧失。此外，随着年龄的增长，这些小鼠出现了严重的多器官功能障碍。 组织炎症我们最近证明，Tim-1在Bcl-2上是凋亡细胞（AC）所必需的。 与Bcirrhosis的结合以及AC诱导的Bcirrhosis中IL-10的产生。两只小鼠的B细胞都不能产生 IL-10对AC的响应。因此，我们假设Tim-1也是最佳布雷格功能的关键和必要的 在维持免疫耐受和限制炎症反应的感应AC，这将解决 在目标1中，使用我们最近产生的Tim-1 floxed小鼠。除了产生IL-10，我们的RNA-seq 分析表明，Tim-1+ Bcl-2还表达许多其他抑制性分子，其中一些 已显示调节IL-10非依赖性布雷格功能。我们还证明， 抑制性分子调节Tim-1+ Bcells中的IL-10。因此，我们假设，Tim-1+ Bceptin发挥其 调节功能不仅通过产生IL-10，而且通过表达一组抑制分子， 给予Bethesda抑制自身免疫反应的最佳能力-这将在目标2中检验。我们的RNA- seq数据集鉴定了一组在Tim-1+ Bcl-2中差异表达的转录因子。因此，我们建议 目的：研究转录因子在BMP 3中的作用。这些研究将大大提高我们的 了解Tim-1在Bcirrhosis中的作用以及Bcirrhosis在免疫耐受和自身免疫中的作用，以及 还可以通过靶向B细胞来提供治疗自身免疫性疾病的新的治疗策略。 !