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

人类 T 细胞再刺激诱导的细胞死亡 (RICD) 的时间和代谢调节

• 批准号: 10582089
• 负责人: Andrew L Snow
• 金额: $ 2.17万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582089
• 关键词: Autoimmunity; B-Lymphocytes; Binding; Biochemical; Cell Count; Cell Death; Cessation of life; Clinical; Defect; Diagnostic; Disease; Disease Outcome; Equilibrium; Event; FOXP3 gene; Genetic; Genetic Transcription; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune system; Infection; Leukocytes; Lymphoproliferative Disorders; Malignant Neoplasms; Metabolic; Metabolism; Molecular; NTB-A; PTPN6 gene; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Predisposition; Process; Public Health; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Role; SH2D1A gene; Severity of illness; Signal Transduction; Signaling Molecule; Single-Gene Defect; T cell response; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Vaccination; X-Linked lymphoproliferative disorders; improved; interest; new therapeutic target; novel; pathogen; programs; receptor; transcription factor

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.

项目总结/摘要PI：Snow，Andrew L. 健康的免疫系统依赖于白色细胞增殖和死亡的平衡。 血细胞，包括B和T淋巴细胞，以遏制和消除传染性病原体 有效地进行，而不会对“自身”组织造成意外损害。我一直对 阐明了维持免疫稳态的分子机制， 人类，重点是B和T细胞。其中一种方式是激活的T细胞被指示死亡， 在T细胞受体（TCR）的重复接合后;称为再刺激的过程- 诱导细胞死亡（RICD）。这种自我调节的死亡计划可以防止过度的死亡。 随着免疫反应的展开，T细胞的扩增。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 增殖和生存至死，这些仍然没有完全理解。 我们的研究部分是通过调查人类免疫系统疾病， 单基因缺陷，导致免疫稳态失调。我们之前发现 来自X连锁淋巴增生性疾病（XLP）患者的T细胞中的新型RICD缺陷， 其缺乏SLAM相关蛋白（SAP）的表达。SAP是正确的RICD所必需的， 正常的T细胞使用各种遗传和生物化学方法，我们阐明了 连接SAP、NTB-A和key的以前未被识别的生化信号网络 激酶（例如LCK、DGKa）、磷酸酶（SHP-1）和转录因子（FOXP 3）， 调节TCR信号传导并最终控制人常规和 调节性T细胞然而，我们也了解到，其他几种信号分子独立于 这个网络控制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，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调节因子是否以及如何 在整个人类T细胞反应中，包括早期阶段， 快速的T细胞增殖。阐明这些关键的信号事件将改善我们的基本 了解免疫疾病患者的异常T细胞信号传导和细胞死亡 超越XLP了解这些分子间的相互作用将为治疗提供新的靶点， 通过操纵RICD敏感性来控制T细胞反应，这可以应用于许多 剔除过量T细胞的临床背景（例如自身免疫、淋巴增生性疾病） 或增强T细胞反应（如感染、接种疫苗、癌症）可能有助于改善疾病。