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：
9749987
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9749987
关键词：
Affect Antigens Apoptosis Apoptotic Attenuated Autoimmune Diseases Autoimmunity B-Lymphocytes Basic Science Binding Biochemical Biochemical Pathway Biological Markers Biology CD94 Antigen Cell Count Cell Death Cell Surface Receptors Cells Cellular Assay 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 chronic infection effector T cell 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

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.

描述（由适用提供）：健康的免疫系统取决于包括T细胞在内的白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，而无需对“自我”组织造成意外损害。指示活化的T细胞被指示死亡的一种方法是在反复接合T细胞受体（TCR）时发生的。一种称为降解诱导的细胞死亡（RICD）的过程。该自我调节的死亡计划可以防止T细胞过多扩展，因为免疫反应展开。该项目的长期目标是定义特定的生化信号那将TCR信号从增殖和生存转化为死亡，迄今为止，这些信号仍然很少理解。我们以前在患有X连锁淋巴细胞增生疾病（XLP）患者的T细胞中发现了一种新的RICD缺陷，该缺乏与大满贯相关蛋白（SAP）的表达。与正常T细胞中适当的RICD需要SAP与SLAM家族受体蛋白NTB-A结合使用。该项目使用人类细胞中的多种遗传和生化方法，旨在进一步阐明和操纵分子机制，通过该机制，SAP和NTB-A直接TCR信号在活化的T细胞中死亡。这项基础研究将阐明连接SAP，NTB-A和关键激酶（例如LCK，DGKA），磷酸酶（SHP-1）以及转录因子（FOXP3）的生化信号网络，最终控制了常规和调节性T细胞中RICD敏感性。此外，我们对众多人类捐助者的拟议调查将确定正常个体中RICD敏感性的SAP和NTB-A是否是有意义的“生物标志物”，这可以为预测T细胞对感染或疫苗接种的T细胞反应的大小提供创新的新诊断工具。阐明这些关键信号事件将改善我们对XLP以外的淋巴细胞增生和自身免疫性疾病患者的T细胞信号传导和细胞死亡异常的基本理解。靶向这些分子相互作用应提供一种新的治疗方法来通过操纵RICD敏感性来控制T细胞反应。这种策略可以应用于众多临床环境中，其中剔除超过T细胞（例如自身免疫性，淋巴细胞增生性疾病）或增强T细胞反应（例如感染，癌症）可以帮助缓解疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FOXP3 protects conventional human T cells from premature restimulation-induced cell death.

FOXP3 保护传统人类 T 细胞免受再刺激引起的过早细胞死亡。

DOI：
10.1038/s41423-019-0316-z
发表时间：
2021
期刊：
Cellular & molecular immunology
影响因子：
24.1
作者：
Voss,Kelsey;Lake,Camille;Luthers,ChristopherR;Lott,NathanielM;Dorjbal,Batsukh;Arjunaraja,Swadhinya;Bauman,BradlyM;Soltis,AnthonyR;Sukumar,Gauthaman;Dalgard,CliftonL;Snow,AndrewL
通讯作者：
Snow,AndrewL

Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells.

DOI：
10.4049/jimmunol.1601218
发表时间：
2017-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Larsen SE;Bilenkin A;Tarasenko TN;Arjunaraja S;Stinson JR;McGuire PJ;Snow AL
通讯作者：
Snow AL

Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening.

通过虚拟筛选鉴定用于 XLP-1 治疗的新型 DGKα 抑制剂。

DOI：
10.1016/j.ejmech.2018.12.061
发表时间：
2019
期刊：
European journal of medicinal chemistry
影响因子：
6.7
作者：
Velnati,Suresh;Ruffo,Elisa;Massarotti,Alberto;Talmon,Maria;Varma,KonduruSaiSandeep;Gesu,Alessandro;Fresu,LuigiaGrazia;Snow,AndrewL;Bertoni,Alessandra;Capello,Daniela;Tron,GianCesare;Graziani,Andrea;Baldanzi,Gianluca
通讯作者：
Baldanzi,Gianluca

Metabolic reprogramming and apoptosis sensitivity: Defining the contours of a T cell response.

DOI：
10.1016/j.canlet.2017.08.033
发表时间：
2017-11-01
期刊：
Cancer letters
影响因子：
9.7
作者：
Voss K;Larsen SE;Snow AL
通讯作者：
Snow AL

FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression.

FOXP3 通过抑制 SAP 表达，使激活的人类调节 T 细胞抵抗再刺激诱导的细胞死亡。

DOI：
10.1016/j.cellimm.2018.02.007
发表时间：
2018
期刊：
Cellular immunology
影响因子：
4.3
作者：
Katz,Gil;Voss,Kelsey;Yan,ToriaF;Kim,YongChan;Kortum,RobertL;Scott,DavidW;Snow,AndrewL
通讯作者：
Snow,AndrewL