The role of ILC3 in autoimmune inflammation

ILC3在自身免疫炎症中的作用

• 批准号: 320374141
• 负责人: Professor Dr. Ari Waisman
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320374141?language=en
• 关键词: role; ILC3; autoimmune; inflammation

Cells that are regulated by the transcription factor ROR gamma (g)t have critical functions in immunity but also can play a harmful role in autoimmune processes. These cells produce the pro-inflammatory cytokines IL-17 and IL-22, which are important not only to maintain the barrier integrity of mucosal surfaces, but can also promote uncontrolled inflammation and contribute to tissue damage. There are four major groups of cells that can express RORgt-dependent IL-17, including on the one hand the adaptive RAG-dependent alpha-beta T cells (Th17 and Tc17) and gamma-delta T cells and on the other hand the group 3 innate lymphoid cells (ILCs), comprising LTi cells and ILC3s. In order to express RORgt most T cells need to be activated by exposure to environmental factors, such as the microbiota. In sharp contrast, group 3 ILCs are characterized by a constitutively active RORgt transcriptional profile, including the expression of IL-22 and to a lower extent IL-17, both being critical in the early responses to infections and tissue injury. Recently, it was shown that ILC3s can express MHC class II molecules, making them potential antigen presenting cells (APCs), a unique feature for lymphoid cells in the mouse. In contrast to other APCs, ILC3s interaction with CD4 T cells, via MHC class II was shown to induce tolerance rather than immunity, therefore suggesting that ILC3s may contribute to novel mechanisms of peripheral tolerance. In the frame of this grant application we plan to study the role of ILC3s as either promoters or suppressors of inflammatory processes, in steady state and pathology, using novel genetic tools generated especially for this project. Furthermore, we will engineer a new system that will allow us to specifically ablate ILC3s to study homeostatic T cell responses as well as autoimmunity in their absence. In addition, we will use conditional gene targeting to either remove MHC class II from ILC3s or force these cells to specifically present an autoantigen. We will then use these mice to study whether antigen presentation by ILC3s results in tolerance of autoreactive T cells in vivo. Finally, we plan to use unique genetic tools to investigate how IL-1 and IL-6 signaling, respectively, affects the development, plasticity and function of ILC3s. Our studies should help to better understand the biology of this rather new cellular player of innate immunity, specifically tackling the role played by ILC3s in inflammation and autoimmunity.

受转录因子RORγ(G)调节的细胞在免疫中具有关键功能，但也可能在自身免疫过程中发挥有害作用。这些细胞产生促炎细胞因子IL-17和IL-22，它们不仅对维持粘膜表面屏障的完整性很重要，而且还可以促进失控的炎症和促进组织损伤。有四种主要的细胞群可以表达RORgt依赖的IL-17，一方面包括适应性RAg依赖的α-βT细胞(Th17和Tc17)和γ-βT细胞，另一方面是第三组先天淋巴样细胞(ILCs)，包括LTI细胞和ILC3细胞。为了表达RORgt，大多数T细胞需要通过暴露于环境因素，如微生物区系而被激活。与之形成鲜明对比的是，第3组ILCs的特征是具有组成活性的RORgt转录谱，包括IL-22的表达，以及较低程度的IL-17的表达，两者在感染和组织损伤的早期反应中都是至关重要的。最近的研究表明，ILC3可以表达MHC-II类分子，使其成为潜在的抗原提呈细胞(APC)，这是小鼠淋巴样细胞的独特特征。与其他APC相比，ILC3s通过MHC II类与CD4T细胞相互作用诱导耐受，而不是免疫，因此提示ILC3s可能参与外周耐受的新机制。在这项拨款申请的框架内，我们计划使用专门为该项目开发的新基因工具，研究ILC3在稳态和病理学中作为炎症过程的促进者或抑制者的作用。此外，我们将设计一种新的系统，使我们能够特异性地去除ILC3，以研究体内平衡的T细胞反应以及在它们缺失的情况下的自身免疫。此外，我们将使用条件性基因打靶来从ILC3中移除MHC II类，或者迫使这些细胞特异性地呈现一种自身抗原。然后，我们将使用这些小鼠来研究ILC3s的抗原提呈是否导致体内自身反应性T细胞的耐受。最后，我们计划使用独特的遗传工具来研究IL-1和IL-6信号分别如何影响ILC3的发育、可塑性和功能。我们的研究应该有助于更好地理解这种相当新的先天免疫细胞参与者的生物学，特别是解决ILC3在炎症和自身免疫中所起的作用。