Control of Treg exhaustion by OX40

描述（申请人提供）：随着强效免疫抑制药物的出现，急性同种异体移植排斥反应在临床上已很少见，移植物的短期存活率也很高。然而，长期移植存活率也是罕见的，随着时间的推移，大多数同种异体移植物不断失去排斥反应。不可否认的是，长期接受贪污仍然存在重大障碍。我们最近发现，Foxp 3 + T细胞，一种致力于免疫调节并与移植耐受密切相关的细胞类型，可以被共刺激分子OX 40驱动到“耗尽”。“耗尽的TGFs”容易失去其调节功能，获得典型的耗尽标志物，如PD-1、Tim-3和KLRG 1，并变得对细胞凋亡敏感。我们通过转录谱分析鉴定了一个新的转录因子Baft 3，并认为其参与Treg耗竭。Batf 3被强烈诱导 OX 40的作用，并与疲劳性甲状腺炎的发展密切相关。我们提供了令人信服的数据，Baft 3物理结合到Foxp 3的启动子区，并积极抑制Foxp 3的表达。基于此，我们假设Treg耗竭是Foxp 3 + Tf 3的一种珍贵的未被识别的命运，并且Treg耗竭是转录调节的，其中Batf 3发挥核心作用。理解OX 40诱导Batf 3的机制以及Batf 3如何驱动TcR耗尽是该提案的中心焦点。我们相信，拟议的研究将揭示新的机制的耐受性，并可能导致新的疗法在诱导移植耐受的发展。此外，这些研究的结果将对其他免疫介导的疾病产生广泛影响，如癌症治疗，自身免疫和疫苗开发。

DESCRIPTION (provided by applicant): With the advent of powerful immunosuppression drugs, acute allograft rejection is rare now in the clinic and the short-term transplant survival hs been excellent. However, long-term transplant survival is also rare and most allografts are continuously lost to rejection as time progresses. It is undeniable that there remain significant barriers to long-term graft acceptance. We recently discovered that Foxp3+ Tregs, a cell type dedicated to immune regulation and critically involved in transplant tolerance, can be driven to "exhaustion" by a costimulatory molecule OX40. The "exhausted Tregs" readily lose their regulatory functions, acquire typical exhaustion markers such as PD-1, Tim-3, and KLRG1, and become susceptible to apoptosis. We identified a new transcription factor Baft3 through transcriptional profiling and believed to be involved in Treg exhaustion. Batf3 is strongly induced by OX40 and closely associated with the development of exhausted Tregs. We provide compelling data that Baft3 physically binds to the promoter region of Foxp3 and actively suppresses Foxp3 expression. Based on this, we hypothesized that Treg exhaustion is a preciously unrecognized fate of Foxp3+ Tregs and that Treg exhaustion is transcriptionally regulated in which Batf3 plays a central role. Understanding the mechanisms of Batf3 induction by OX40 and how Batf3 drives Tregs to exhaustion is the central focus of this proposal. We believe that the proposed studies will unravel novel mechanisms of tolerance resistance and may lead to the development of new therapies in the induction of transplant tolerance. In addition, findings from these studies will have broad impact on other immune-mediated diseases, such as cancer therapies, autoimmunity, and vaccination development.