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: 9321362
• 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/9321362
• 关键词: Affect; Antigens; Apoptosis; Apoptotic; Attenuated; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Basic Science; Binding; Biochemical; Biochemical Pathway; Biological Assay; Biological Markers; Biology; CD94 Antigen; 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; Homeostasis; Human; Immune; Immune response; Immune system; Impairment; Individual; Infection; Interleukin-2; Knowledge; Leukocytes; Lymphocyte; Lymphomagenesis; Lymphoproliferative Disorders; Malignant Neoplasms; Molecular; Molecular Target; 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; SLAM protein; Severity of illness; Signal Transduction; Small Interfering RNA; Surveys; T cell response; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Vaccination; Work; X-Linked lymphoproliferative disorders; adaptive immune response; base; immunopathology; immunotoxicity; improved; innovation; novel; novel diagnostics; novel therapeutic intervention; null mutation; pathogen; predictive tools; prevent; programs; promoter; protein expression; public health relevance; receptor; 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（由申请人提供）：健康的免疫系统依赖于白色血细胞（包括T细胞）增殖和死亡的平衡，以有效地遏制和消除感染性病原体，而不会对“自身”组织造成意外损害。活化的T细胞被指示死亡的一种方式发生在T细胞受体（TCR）的重复接合上;这一过程称为再刺激诱导的细胞死亡（RICD）。这种自我调节的死亡程序可以防止T细胞在免疫反应展开时过度扩张。该项目的长期目标是确定特定的生化信号 其将TCR信号从增殖和存活转变为死亡，迄今为止对这一点仍知之甚少。 我们以前发现了一种新的RICD缺陷的T细胞与X-连锁淋巴细胞增生性疾病（XLP），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细胞中适当RICD所需的。在人类细胞中使用各种遗传和生物化学方法，该项目旨在进一步阐明和操纵SAP和NTB-A在活化T细胞中指导TCR死亡信号传导的分子机制。这项基础研究将阐明一个以前未被认识的生化信号网络，这些信号连接SAP、NTB-A和关键激酶（例如LCK、DGKa）、磷酸酶（SHP-1）和转录因子（FOXP 3），最终控制常规和调节性T细胞中的RICD敏感性。此外，我们提出的对众多人类供体的调查将确定SAP和NTB-A是否以及如何成为正常个体中RICD敏感性的有意义的“生物标志物”，这可以为预测T细胞对感染或疫苗接种的反应程度提供创新的新诊断工具。阐明这些关键信号事件将提高我们对XLP以外的淋巴增生性和自身免疫性疾病患者中异常T细胞信号传导和细胞死亡的基本理解。靶向这些分子相互作用应该提供一种新的治疗方法，通过操纵RICD敏感性来控制T细胞反应。这种策略可以应用于许多临床环境，其中剔除多余的T细胞（例如自身免疫，淋巴增生性疾病）或增强T细胞应答（例如感染，癌症）可以帮助改善疾病。