Regulation of systemic lupus via ICOS triggering by mononuclear phagocytes and B cells

通过单核吞噬细胞和 B 细胞触发 ICOS 调节系统性狼疮

• 批准号: 261036931
• 负责人: Dr. Lino Lars Teichmann
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik III - Innere Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/261036931?language=en
• 关键词: Regulation; systemic; lupus; via; ICOS

Systemic lupus erythematosus (SLE) is a relapsing-remitting autoimmune syndrome that leads to multi-organ inflammation and damage. Most frequently women of child-bearing age are affected. Current treatment options for SLE are often not effective or have serious side effects. T cells are key players in the genesis of lupus promoting autoantibody production and directly exerting pathogenic effects. Their activity is controlled by a variety of antigen-presenting cell (APCs) types, such as dendritic cells and macrophages, both of which belong to the mononuclear phagocyte system (MPS), and B cells. We have previously shown that activation of naïve CD4 T cells in lupus-prone MRL.Faslpr mice is entirely dependent on B cells whereas MPS cells are dispensable. However, constitutive deletion of MPS cells greatly impedes T cell expansion and functional differentiation, resulting in substantially less organ inflammation. Specifically which molecular interactions between discrete types of APCs and T cells critically contribute to disease development and what the relevant downstream mechanisms are remains largely unknown. In the proposed study we will therefore investigate to what extent and how triggering of the T cell-expressed co-stimulatory receptor ICOS by its ligand ICOSL on MPS or B cells promotes lupus. For this purpose we have generated MRL.Faslpr mice deficient for the gene Icosl selectively in MPS or B cells. Preliminary results suggest that ICOS ligation by MPS but not B cells drives nephritis. We will expand on these findings and initially evaluate the importance of ICOSL on MPS and B cells for inflammation in multiple lupus target-organs and for the occurrence of various autoantibody specificities and isotypes. Because ICOS stimulates the PI(3)K-Akt signaling pathway we will then test whether ICOS ligation by MPS or B cells is essential for cell cycle progression and survival of activated T cells in lymphoid and peripheral organs. Next, we will analyze whether differentiation of T extrafollicular (TEFH) helper cells (a T cell subset in the splenic red pulp of lupus mice that assists autoantibody formation) and T follicular-like (TFH-like) cells, which we just recently discovered in inflamed peripheral organs of MRL.Faslpr mice, depends on ICOSL on MPS and B cells. Finally, we will examine the hitherto undefined functions of TFH-like cells, their transcriptional relatedness to TEFH cells and the ubiquity of their involvement in autoimmune inflammation. These studies are important because they uncover the requirements for T cell-mediated inflammation and new ways to intervene therapeutically.

系统性红斑狼疮（SLE）是一种复发-缓解型自身免疫综合征，可导致多器官炎症和损伤。育龄妇女最常受到影响。目前SLE的治疗方案往往无效或有严重的副作用。T细胞是狼疮发生的关键参与者，促进自身抗体产生并直接发挥致病作用。它们的活性由多种抗原呈递细胞（APC）类型控制，例如树突状细胞和巨噬细胞（两者都属于单核吞噬细胞系统（MPS））和B细胞。我们先前已经表明，在狼疮易感的MRL.Faslpr小鼠中，初始CD 4 T细胞的活化完全依赖于B细胞，而MPS细胞是非活化的。然而，MPS细胞的组成性缺失极大地阻碍了T细胞扩增和功能分化，导致实质上更少的器官炎症。具体而言，离散类型的APC和T细胞之间的哪些分子相互作用对疾病的发展至关重要，以及相关的下游机制在很大程度上仍然未知。因此，在拟议的研究中，我们将研究在多大程度上以及如何触发T细胞表达的共刺激受体ICOS通过其配体ICOSL对MPS或B细胞促进狼疮。为此目的，我们在MPS或B细胞中选择性地产生了基因Icosl缺陷的MRL.Faslpr小鼠。初步结果表明，ICOS由MPS而不是B细胞连接导致肾炎。我们将扩展这些发现，并初步评估ICOSL对MPS和B细胞在多个狼疮靶器官炎症和各种自身抗体特异性和同种型发生的重要性。由于ICOS刺激PI（3）K-Akt信号通路，我们将测试MPS或B细胞的ICOS连接是否对淋巴和外周器官中活化T细胞的细胞周期进展和存活至关重要。接下来，我们将分析T滤泡外（TEFH）辅助细胞（狼疮小鼠脾红髓中有助于自身抗体形成的T细胞亚群）和T滤泡样（TFH样）细胞的分化是否取决于MPS和B细胞上的ICOSL，这些细胞是我们最近在MRL.Faslpr小鼠的炎症外周器官中发现的。最后，我们将研究迄今为止尚未确定的功能TFH样细胞，其转录相关性TEFH细胞和普遍存在的参与自身免疫性炎症。这些研究很重要，因为它们揭示了T细胞介导的炎症的要求和治疗干预的新方法。