Control of Treg exhaustion by OX40

描述(申请人提供)：随着强大的免疫抑制药物的出现，急性同种异体移植排斥反应现在在临床上很少见，短期移植存活一直很好。然而，移植物的长期存活也是罕见的，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。这是一个清醒的提醒，在接受贪污方面仍然存在巨大的障碍。我们最近发现，Foxp3+Tregs是一种致力于免疫调节的细胞类型，也是移植耐受的关键因素，它可以被共刺激受体OX40驱动到耗尽的表型。这种耗竭的Treg很容易失去它们的调节功能，获得典型的耗竭标志物，如PD-1、Tim-3和KLRG1，并对细胞凋亡变得极其敏感。通过转录谱分析，我们发现了一种新的转录因子Baft3，该转录因子在Tregs中受OX40强烈诱导，并与力竭Tregs的发生密切相关。我们提供了Baft3与Foxp3的启动子区域物理结合并主动抑制Foxp3表达的初步数据。在此基础上，我们假设Treg耗竭是Foxp3+Treg的另一种命运，Treg耗竭是转录调控的，其中BATF3起核心作用。了解OX40诱导BATF3的机制以及BATF3如何驱动Tregs耗尽是本应用的中心焦点。我们相信，拟议的研究将揭开耐受耐受的新机制，并可能导致诱导移植耐受的新疗法的开发。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，例如癌症治疗和保护性免疫。

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. This is a sober reminder that there remain significant barriers to graft acceptance. We recently discovered that Foxp3+ Tregs, a cell type dedicated to immune regulation and also critically involved in transplant tolerance, can be driven to an exhausted phenotype by the costimulatory receptor OX40. Such exhausted Tregs readily lose their regulatory functions, acquire typical exhaustion markers such as PD-1, Tim-3, and KLRG1, and become extremely sensitive to apoptosis. Through transcriptional profiling, we identified a new transcription factor, namely Baft3 that is strongly induced by OX40 in Tregs and closely associated with the development of exhausted Tregs. We provide preliminary 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 an alternative fate of Foxp3+ Tregs and 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 application. 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 impacts on other immune-mediated diseases, such as cancer therapies and protective immunity.