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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

基本信息

批准号：
9029392
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
项目类别：
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/9029392
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 Family Genes Genetic Goals 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 Relative (related person)Reporter Research Resistance Role Severity of illness Signal Transduction Signaling Molecule Signaling Protein 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 public health relevance receptor tool transcription factor tumor

项目摘要

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.