SAP/NTB-A Signaling in T Cell Restimulation-Induced Cell Death

T 细胞再刺激诱导的细胞死亡中的 SAP/NTB-A 信号转导

• 批准号: 9144410
• 负责人: Andrew L Snow
• 金额: $ 31.15万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144410
• 关键词: Affect; Antigens; Apoptosis; Apoptotic; Attenuated; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Basic Science; Binding; Biochemical; Biochemical Pathway; Biological Assay; Biological Markers; Biology; Cell Count; Cell Death; Cell Surface Receptors; Cells; Cessation of life; Chronic; Clinical; Complex; Data; Defect; Dependence; Diacylglycerol Kinase; Diagnostic; Disease; Disease Outcome; Ectopic Expression; Equilibrium; Event; FOXP3 gene; Family; Genes; Genetic; Goals; Health; Homeostasis; Human; Immune; Immune response; Immune system; Individual; Infection; Interleukin-2; Knowledge; Leukocytes; Lymphocyte; Lymphocyte Activation; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Molecular; Mus; Mutation; Natural Killer Cells; PTPN6 gene; Pathology; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Plasmids; Population; Process; Proteins; Public Health; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Regulatory T-Lymphocyte; Reporter; Research; Resistance; Role; SH2D1A gene; Severity of illness; Signal Transduction; Small Interfering RNA; Surveys; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Vaccination; Work; X-Linked lymphoproliferative disorders; adaptive immunity; base; immunopathology; immunotoxicity; improved; innovation; intercellular communication; novel; novel diagnostics; novel therapeutic intervention; null mutation; pathogen; prevent; programs; promoter; protein expression; receptor; tool; transcription factor; tumor

 DESCRIPTION (provided by applicant): The healthy immune system depends upon a balance of proliferation and death of white blood cells, including T cells, to contain and eliminate infectious pathogens effectively without doing unintended damage to "self" tissues. 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 this project is to define specific biochemical signals that convert the TCR signal from proliferation and survival to death, which to date remain poorly understood. 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, in conjunction with the SLAM family receptor protein NTB-A, is required for proper RICD in normal T cells. Using a variety of genetic and biochemical approaches in human cells, this project aims to further elucidate and manipulate the molecular mechanism by which SAP and NTB-A direct TCR signaling for death in activated T cells. This basic research will illuminate 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 ultimately govern RICD sensitivity in conventional and regulatory T cells. Moreover, our proposed survey of numerous human donors will determine if and how SAP and NTB-A are meaningful "biomarkers" of RICD sensitivity in normal individuals, which could provide an innovative new diagnostic tool for predicting the magnitude of T cell responses to infection or vaccination. Elucidating these critical signaling events will improve our basic understanding of abnormal T cell signaling and cell death in patients with lymphoproliferative and autoimmune disorders beyond XLP. Targeting these molecular interactions should offer a new therapeutic approach to control T cell responses by manipulating RICD sensitivity. Such a strategy 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, cancer) could help ameliorate disease.

 描述(申请人提供)：健康的免疫系统依赖于包括T细胞在内的白细胞的增殖和死亡的平衡，以有效地遏制和消除传染性病原体，而不会对“自身”组织造成意外的损害。激活的T细胞被指示死亡的一种方式发生在T细胞受体(TCR)的重复参与；这一过程被称为重新刺激诱导细胞死亡(RICD)。随着免疫反应的展开，这种自我调节的死亡程序可以防止T细胞过度扩张。该项目的长期目标是定义特定的生化信号 这将TCR信号从增殖和存活转化为死亡，到目前为止，人们对此仍知之甚少。我们先前在X连锁淋巴增生性疾病(XLP)患者的T细胞中发现了一种新的RICD缺陷，该缺陷缺乏SLAM相关蛋白(SAP)的表达。SAP与SLAM家族受体蛋白NTB-A结合，是正常T细胞发生RICD所必需的。利用人类细胞中的各种遗传和生化方法，该项目旨在进一步阐明和操纵SAP和NTB-A在激活的T细胞中直接发出TCR信号导致死亡的分子机制。这项基础研究将阐明一个以前未知的生化信号网络，这些信号连接SAP、NTB-A和关键激酶(如LCK、DGKA)、磷酸酶(SHP-1)和转录因子(FOXP3)，最终控制常规和调节性T细胞对RICD的敏感性。此外，我们拟议的对众多人类捐赠者的调查将确定SAP和NTB-A是否以及如何成为正常人RICD敏感性的有意义的“生物标记物”，这可能为预测T细胞对感染或疫苗的反应量提供一种创新的新诊断工具。阐明这些关键信号事件将提高我们对XLP以外淋巴增殖性和自身免疫性疾病患者T细胞信号异常和细胞死亡的基本理解。靶向这些分子相互作用将提供一种新的治疗方法，通过控制RICD的敏感性来控制T细胞反应。这种策略可以应用于许多临床情况，在这些情况下，剔除多余的T细胞(例如，自身免疫、淋巴增生性疾病)或增强T细胞反应(例如，感染、癌症)可以帮助改善疾病。