Role of Tim-1 and Bregs in Tolerance and Autoimmunity

项目总结 越来越多的证据支持，调节性B细胞(Bregs)对于限制炎症和 自身免疫通过IL-10依赖和非依赖的方式实现。缺乏一个通用的标记来识别 然而，Bregs阻碍了我们对其关键生物学功能的理解。流程和 Bregs的产生机制也尚未确定。Rothstein博士的实验室以及我们的 OWN的研究表明，TIM-1识别产生IL-10的Bregs。我们产生了一只功能丧失的小鼠 TIM-1突变体(TIM-1∆粘蛋白)，发现TIM-1∆粘蛋白和传统的TIM-1缺陷(TIM-1-/-)均表现出 B细胞产生IL-10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 组织发炎。我们最近已经证明Bregs上的TIM-1是凋亡细胞(AC)所必需的 与Bregs结合和AC诱导Bregs产生IL-10。两只小鼠的B细胞都不能产生 IL-10对AC的反应。因此，我们假设TIM-1对于最优Breg函数也是关键和必要的 通过感知AC来维持免疫耐受和限制炎症反应，这将被解决 在目标1中，使用我们最近培育的Tim-1牙线小鼠。除了产生IL-10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IL-10非依赖的BREG功能。我们还展示了一些 抑制分子调节TIM-1 Bregs中的IL-10。因此，我们假设TIM-1 Bregs使用他们的 调节功能不仅通过产生IL-10，还通过表达一组抑制分子，其中 赋予Bregs抑制自身免疫反应的最佳能力-这将在Aim 2中进行检验。我们的RNA- SEQ数据集发现了一组在Tim-1 Bregs中差异表达的转录因子。因此，我们建议 研究Bregs转录因子在目标3中的作用。这些研究将极大地增加我们的 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 通过靶向B细胞治疗自身免疫性疾病，也可能提供一种新的治疗策略。 好了！

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. !