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

系统性红斑狼疮(SLE)是一种复发缓解的自身免疫综合征，可导致多器官炎症和损害。最常见的情况是育龄妇女受到影响。目前治疗系统性红斑狼疮的选择往往无效或有严重的副作用。T细胞在狼疮的发生中起关键作用，促进自身抗体的产生，并直接发挥致病作用。它们的活性受多种抗原提呈细胞(APC)类型的控制，如树突状细胞和巨噬细胞，这两种细胞都属于单核巨噬细胞系统(MPS)，以及B细胞。我们先前已经证明，在易患狼疮的MRL.Faslpr小鼠中，幼稚的CD4T细胞的激活完全依赖于B细胞，而MPS细胞是必不可少的。然而，MPS细胞的结构性缺失极大地阻碍了T细胞的扩增和功能分化，导致器官炎症显著减少。具体地说，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起关键作用，以及相关的下游机制在很大程度上仍不清楚。因此，在拟议的研究中，我们将研究MPS或B细胞上T细胞表达的共刺激受体ICOS被其配体ICOSL触发在何种程度上以及如何促进狼疮的发生。为此，我们培育了MPS或B细胞中选择性缺失IcoS基因的MRL.Faslpr小鼠。初步结果表明，MPS而不是B细胞通过ICOS结扎可导致肾炎。我们将对这些发现进行扩展，并初步评估ICOSL在多个狼疮靶器官的炎症以及各种自身抗体特异性和亚型的发生中对MPS和B细胞的重要性。由于ICOS刺激PI(3)K-Akt信号通路，因此我们将测试MPS或B细胞对ICOS的连接是否对淋巴和外周器官中激活的T细胞的细胞周期进程和生存至关重要。接下来，我们将分析最近在MRL.Faslpr小鼠炎症的外周器官中发现的T滤泡外(TEFH)辅助细胞(狼疮小鼠脾红髓中帮助自身抗体形成的T细胞亚群)和T滤泡样细胞(TFH样细胞)的分化是否依赖于MPS和B细胞上的ICOSL。最后，我们将研究迄今尚未确定的TFH样细胞的功能，它们与TEFH细胞的转录相关性，以及它们参与自身免疫性炎症的普遍性。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。

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.