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在临床上已经很少见，移植短期生存率很好。然而，长期的移植存活也是罕见的，大多数同种异体移植物随着时间的推移不断丧失排斥反应。不可否认的是，长期接受移植仍然存在重大障碍。我们最近发现Foxp3+ Tregs，一种致力于免疫调节并关键参与移植耐受的细胞类型，可以被共刺激分子OX40驱动到“衰竭”。“衰竭treg”很容易失去其调节功能，获得典型的衰竭标志物，如PD-1、Tim-3和KLRG1，并容易发生凋亡。我们通过转录分析发现了一个新的转录因子Baft3，并认为它与Treg耗竭有关。Batf3是强诱导的

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.