Molecular chaperones and immune tolerance

分子伴侣和免疫耐受

• 批准号: 9310818
• 负责人: Zihai Li
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310818
• 关键词: Address; Applications Grants; Area; Attention; Attenuated; Autoimmune Diseases; B-Lymphocytes; Binding; Binding Proteins; Biological Availability; Biology; Blood Platelets; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell physiology; Cell surface; Cells; Cellular biology; Client; Collaborations; Cross Presentation; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Docking; Drops; Endoplasmic Reticulum; Equilibrium; FOXP3 gene; Funding; Genetic Models; Heat shock proteins; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologist; Infection; Inflammation; Integrins; Interleukin-12; Investigation; Knockout Mice; LRRC32 gene; Laboratories; Ligation; Link; Lupus; Malignant Neoplasms; Modeling; Molecular; Molecular Chaperones; Mus; Myelogenous; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathogenicity; Pathologic; Patients; Peptides; Peripheral; Play; Population; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; System; Systemic Lupus Erythematosus; TLR4 gene; Time; Toll-like receptors; Transforming Growth Factor beta; Yang; base; cell type; clinically relevant; extracellular; fight against; in vivo; lupus-like; mouse model; novel; paracrine; prevent; proteostasis; receptor; stress protein

PROJECT SUMMARY gp96 is an immune chaperone in the lumen of the endoplasmic reticulum, for the folding and assembly of multiple key receptors in immune responses including TLRs and integrins. Dysregulation of gp96 has been linked with a number of rheumatoid diseases such as lupus. We discovered very recently that gp96 is also critically required for the stability and in vivo suppressive function of regulatory T cells (Zhang et al., J Clin Invest 2015). Furthermore, we unveiled that gp96 serves as an essential chaperone for folding the cell surface docking receptor for TGFb, GARP (known also as LRRC32), whose expression is thought to be restricted to Tregs and platelets. Intriguingly, we found that B cells but not myeloid cells express GARP upon TLR ligation, and there is a unique population of GARP+ B cells in the steady state in both mouse lupus models and human patients with SLE. In essence, we have now established that gp96 regulates several key aspects of immunity and tolerance. It is required for optimal dendritic cell activation via chaperoning TLRs to initiate immune responses. gp96 also plays essential roles for immune tolerance by endowing suppressive function of Treg cells. The immunity vs. tolerance fate determination thus could be orchestrated by gp96 in a contextual and cell type specific fashion. We hypothesize that gp96 controls immune tolerance by regulating the bioavailability of cell surface TGFb for Tregs and B cells. This is accomplished by the intrinsic chaperone function of gp96 in folding both GARP and integrins, the former is involved in snatching and binding latent TGFb from the extracellular milieu in a paracrine fashion, whereas the latter is involved in TGFb activation. This novel hypothesis will be addressed by the following two specific aims: Our first Aim will focus on understanding the mechanisms of gp96 in controlling Treg cell function. Our second Aim will determine the roles of B cell-intrinsic GARP in fundamental B cell biology and the pathogenesis of lupus, by taking advantage of our exciting preliminary data demonstrating the roles of GARP in attenuating experimental lupus. Thus, the two aims will be pursued in both normal and pathogenic conditions. A number of novel genetic models including inducible and cell-specific GARP knockout mice, will be used. We believe that full elucidation of our hypothesis will have fundamental implications in understanding the elusive roles of cell surface TGFb in immune tolerance, as well as in the pathogenesis of lupus.

项目摘要 GP96是内质网腔中的免疫伴侣，用于折叠和组装 免疫反应中的多个关键受体，包括TLR和整合素。 GP96的失调一直是 与许多类风湿病（例如狼疮）有关。我们最近发现GP96也是 至关重要的是调节T细胞的稳定性和体内抑制功能（Zhang等，J Clin 投资2015）。此外，我们公布了GP96是折叠细胞表面的必不可少的伴侣 TGFB，GARP的对接受体（也称为LRRC32），其表达被认为仅限于 特雷格和血小板。有趣的是，我们发现B细胞而不是髓样细胞在TLR连接时表达GARP， 在小鼠狼疮模型和人类中，稳定状态下有独特的GARP+ B细胞群体 SLE患者。 从本质上讲，我们已经确定GP96调节免疫和宽容的几个关键方面。这是 通过伴侣TLRS启动免疫反应的最佳树突状细胞激活所必需的。 GP96也是如此 通过赋予Treg细胞的抑制作用来发挥免疫耐受性的重要作用。免疫力与 因此，宽容命运的确定可以由GP96以上下文和细胞类型的方式策划。 我们假设GP96通过调节细胞表面TGFB的生物利用度来控制免疫耐受性 Tregs和B细胞。这是通过GP96的固有伴侣函数在折叠GARP和 整联蛋白，前者参与了从一个细胞外环境中抢夺和绑定潜在的TGFB 旁分泌方式，而后者参与TGFB激活。这个新颖的假设将由 以下两个具体目标： 我们的第一个目标将集中于了解GP96在控制Treg细胞功能方面的机制。我们的第二个 AIM将确定B细胞中GARP在基本B细胞生物学和发病机理中的作用 狼疮，利用我们令人兴奋的初步数据，证明了GARP在衰减中的作用 实验性狼疮。因此，这两个目标将在正常和致病条件下被追求。许多 将使用包括诱导型和细胞特异性GARP敲除小鼠在内的新型遗传模型。我们相信 完全阐明我们的假设将对理解细胞的难以捉摸的作用具有根本的影响 免疫耐受性以及狼疮的发病机理中的表面TGFB。