T cell fate decisions and transplant outcomes

项目摘要 排斥反应仍然是长期移植存活的主要障碍。从临床角度来看， 免疫抑制方案在短期移植存活率方面非常好，但在促进长期移植存活方面却收效甚微。 长期移植结果。因此，迫切需要揭示可能出现的效应程序， 广泛的免疫抑制条件，可以介导移植物丢失，目标是进一步改善长期 移植结果我们最近发现，与其他Th亚群不同，Th 9细胞在体内被强烈诱导， 免疫抑制环境，表明Th 9细胞可能与移植物丢失特别相关， 免疫抑制的条件。当默认的Th 1/Th 2/Th 3/Th 4/Th 5/Th 7/Th 8/Th 9/Th 程序被抑制并且需要在Il 9基因座处形成超级增强子（非谱系特异性 转录因子）。重要的是，Il 9超级增强子的形成需要0X 40信号传导。OX 40是 在将Foxp 3 + T细胞重定向至炎性Th 9细胞方面具有显著效力。基于这种意想不到的效力 在稳健的Th 9诱导中的OX 40，以及OX 40刺激的意外作用模式，我们 我建议在这个建议中测试一个统一的假设，即-抑制默认的T细胞程序， 免疫抑制环境允许OX 40促进替代性Th 9程序，触发免疫排斥， 其他耐受性移植物。我们在这个建议中提出了三个目标。目标1侧重于识别新的 OX 40促进大量Th 9细胞的机制，研究了OX 40的形成，结构和活性。 Il 9基因座处的超级增强子。目的2研究了OX 40如何将Foxp 3 + T细胞重定向至Th 9细胞， 新鉴定的Foxp 3阻遏物在关闭Foxp 3表达中的作用，并检查Foxp 3 可能破坏IL-9超级增强子的形成。目的3检查Th 9细胞在移植存活中的影响， 测试在Th 9诱导中靶向超级增强子或检查点是否能够实现稳健的同种异体移植 宽容我们相信，拟议的研究将揭示新的耐药机制， 这些研究的结果将对其他免疫介导的疾病产生广泛的影响。 疾病，包括癌症免疫疗法和自身免疫性疾病。

Project Summary Rejection remains a major hurdle to long-lasting transplant survival. From a clinical standpoint current immunosuppression protocols are fantastic in short-term transplant survival, but do little in promoting long- term graft outcomes. Thus, there is a pressing need to uncover effector programs that may emerge under broad immunosuppressive conditions that can mediate graft loss, with a goal of further improving long term transplant outcomes. We recently discovered that unlike other Th subsets, Th9 cells are robustly induced in an immunosuppressive milieu, suggesting that Th9 cells may be especially relevant to graft loss under conditions of immunosuppression. Th9 cells are induced in massive numbers when the default Th1/Th2 programs are inhibited and require the formation of super-enhancers at Il9 locus (not lineage specific transcription factors). Importantly, formation of Il9 super-enhancers requires OX40 signaling. Also, OX40 is remarkably potent in redirecting Foxp3+ Tregs to inflammatory Th9 cells. Based on the unexpected potency of OX40 in robust Th9 induction, as well as the unexpected mode of actions of OX40 stimulation, we propose to test a unifying hypothesis in this proposal, namely- suppression of the default T cell programs in an immunosuppressive milieu allows OX40 to promote alternative Th9 programs in triggering rejection of otherwise tolerant grafts. We propose 3 Aims in this proposal. Aim 1 focuses on identifying novel mechanisms by which OX40 promotes massive Th9 cells, examining formation, structure, and activities of super-enhancers at Il9 locus. Aim 2 investigates how OX40 redirects Foxp3+ Tregs to Th9 cells, focusing on the newly identified Foxp3 repressors in shutting down Foxp3 expression and examine whether Foxp3 may disrupt IL-9 super enhancer formations. Aim 3 examines the impact of Th9 cells in transplant survival, testing whether targeting super-enhancers or checkpoints in Th9 induction enables robust allograft tolerance. We believe that the proposed studies will unravel new mechanisms of tolerance resistance in transplant recipients, and findings from these studies will have broad impacts on other immune-mediated diseases as well, including cancer immunotherapies and autoimmune diseases.