Temporal and Metabolic Regulation of Restimulation-Induced Cell Death (RICD) in Human T Cells

项目摘要/摘要PI：Snow，Andrew L. 健康的免疫系统依赖于白血球的增殖和死亡之间的平衡 血细胞，包括B和T淋巴细胞，以遏制和消除感染病原体 有效而不会对“自身”组织造成意外损害。我一直以来都对 阐明维持免疫动态平衡的分子机制 人类，专注于B和T细胞。激活的T细胞被指示死亡的一种方式发生 当T细胞受体(TCR)反复激活时；这一过程被称为重新刺激- 诱导细胞死亡(RICD)。这种自我调节的死亡计划可以防止过度死亡 随着免疫反应的展开，T细胞的扩张。我研究的长期目标是 程序是定义特定的生化信号，将TCR信号从 增殖和存活到死亡，这一点仍然不完全清楚。 我们的研究在一定程度上是通过调查人类免疫疾病而获得的，这些疾病是由 单基因缺陷，导致免疫动态平衡失调。我们之前发现 X连锁淋巴增生性疾病(XLP)患者T细胞中一种新的RICD缺陷 缺乏SLAM相关蛋白(SAP)表达。SAP是正确的RICD在 正常的T细胞。使用各种遗传和生化方法，我们阐明了一种 连接SAP、NTB-A和KEY的以前未被识别的生化信号网络 激酶(如LCK、DGKA)、磷酸酶(SHP-1)和转录因子(FOXP3) 调节TCR信号转导并最终控制人类常规和慢性RICD的敏感性 调节性T细胞。然而，我们也了解到，其他几个独立的信号分子 该网络控制RICD。此外，我们发现细胞内的动态变化 新陈代谢也起着重要作用。在未来五年里，我们的研究将集中在 确定特定的共抑制受体、转录调节因子和代谢是否以及如何 电路对整个人类T细胞反应的RICD敏感性进行“调节”，包括早期阶段 T细胞的快速增殖。阐明这些关键的信号事件将改善我们的基本 对免疫紊乱患者T细胞信号转导异常和细胞死亡的认识 超越XLP。了解这些分子相互作用将为治疗 通过控制RICD敏感性来控制T细胞反应，这可以应用于许多 剔除过剩T细胞的临床背景(例如自身免疫、淋巴增生性疾病) 或者增强T细胞反应(例如感染、接种疫苗、癌症)可以帮助改善疾病。

PROJECT SUMMARY/ABSTRACT PI: Snow, Andrew L. The healthy immune system depends upon a balance of proliferation and death of white blood cells, including B and T lymphocytes, to contain and eliminate infectious pathogens effectively without doing unintended damage to “self” tissues. I have a long-standing interest in elucidating the molecular mechanisms responsible for maintaining immune homeostasis in humans, focusing on B and T cells. One way that activated T cells are instructed to die occurs upon repeated engagement of the T cell receptor (TCR); a process known as restimulation- induced cell death (RICD). This self-regulatory death program protects against excessive expansion of T cells as an immune response unfolds. The long-term objective of my research program is to define specific biochemical signals that convert the TCR signal from proliferation and survival to death, which remain incompletely understood. Our research is informed in part by investigating human immune disorders, caused by single gene defects, that result in dysregulated immune homeostasis. We previously discovered a novel RICD defect in T cells from patients with X-linked lymphoproliferative disease (XLP), which lack expression of SLAM-associated protein (SAP). SAP is required for proper RICD in normal T cells. Using a variety of genetic and biochemical approaches, we illuminated a previously unrecognized network of biochemical signals connecting SAP, NTB-A, and key kinases (e.g. LCK, DGKa), phosphatases (SHP-1), and transcription factors (FOXP3) that regulate TCR signaling and ultimately govern RICD sensitivity in human conventional and regulatory T cells. However, we also learned that several other signaling molecules independent of this network control RICD. Moreover, we discovered that dynamic changes in cellular metabolism also play a major role. Over the next five years, our research will be focused on determining if and how specific co-inhibitory receptors, transcriptional regulators, and metabolic circuits “tune” RICD susceptibility over the entire human T cell response, including early stages of rapid T cell proliferation. Elucidating these critical signaling events will improve our basic understanding of abnormal T cell signaling and cell death in patients with immune disorders beyond XLP. Understanding these molecular interactions should offer new therapeutic targets to control T cell responses by manipulating RICD sensitivity, which could be applied to numerous clinical contexts in which culling excess T cells (e.g. autoimmunity, lymphoproliferative disease) or boosting T cell responses (e.g. infection, vaccination, cancer) could help ameliorate disease.