Regulation of T cell activation and exhaustion by Tim-3

Tim-3 对 T 细胞激活和耗竭的调节

基本信息

批准号：
10220690
负责人：
Lawrence P. Kane
金额：
$ 38.84万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220690
关键词：
Acute Address Animals BLR1 gene Bacteria Binding CD8-Positive T-Lymphocytes Cell Surface Proteins Cell physiology Cells Cellular Immunity Chronic Complex Cytoplasmic Tail Dangerousness Data Ectopic Expression Effector Cell Epitopes Excision FRAP1 gene Functional disorder Gene Expression Generations Genetic Transcription HIV Immune Immune response Immune system Impairment Individual Infection Integral Membrane Protein Knock-out Knowledge Lead Life Ligands Lymphocytic choriomeningitis virus Malignant Neoplasms Mediating Memory Molecular Monoclonal Antibodies Mucins Mus PD-1 pathway PD-L1 blockade Pathology Pathway interactions Phenotype Phospho-Specific Antibodies Physiological Play Population Process Proteins Regulation Role Signal Pathway Signal Transduction Study models T cell regulation T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte TCF3 gene Testing Tissues Viral Virus Virus Diseases acute infection base cell population study checkpoint receptors chronic infection exhaust exhaustion experimental study extracellular gain of function immune checkpoint in vivo inhibitor/antagonist neoplasm immunotherapy pathogen programmed cell death protein 1 programs response stem transcription factor tumor tumor microenvironment

项目摘要

Abstract The transmembrane protein Tim-3 is expressed on a subset of activated T cells, and is particularly enriched on so-called exhausted T cells, which are associated with chronic viral infection and the tumor microenvironment. As such, Tim-3 is being actively explored as a potential target for tumor immunotherapy. However, significant questions remain about how Tim-3 expression is regulated during acute vs. chronic infection, and how signaling pathways downstream of Tim-3 modulate T cell function. Using LCMV infection, we have found that Tim-3 expression and signaling augment early T cell activation during both primary and recall responses, but that Tim-3 is dispensable for the development of T cell exhaustion. Furthermore, we have found that the transcription factor Blimp1 can control Tim-3 expression under some, but not all, circumstances. Here we will further define the effects of Tim-3 on sculpting the overall CD4+ and CD8+ T cell responses to specific viral epitopes of LCMV. We will also define the specific requirements for Blimp1 and downstream factors, including the E-box binding factor inhibitor Id3. Finally, we will determine the role of signaling through the cytoplasmic tail of Tim-3 in regulating T cell activation, memory and exhaustion.

抽象的跨膜蛋白 Tim-3 在激活的 T 细胞亚群上表达，并且是特别富含所谓的耗尽 T 细胞，这些细胞与慢性病毒有关感染与肿瘤微环境。因此，Tim-3 正在被积极探索作为肿瘤免疫治疗的潜在靶点。然而，关于如何 Tim-3 表达在急性与慢性感染期间受到调节，以及信号传导如何进行 Tim-3 下游通路调节 T 细胞功能。使用 LCMV 感染，我们有发现 Tim-3 表达和信号传导增强了早期 T 细胞的激活初级反应和回忆反应，但 Tim-3 对于 T 细胞的发育是可有可无的精疲力尽。此外，我们还发现转录因子Blimp1可以控制 Tim-3 在某些但不是全部情况下表达。这里我们进一步定义 Tim-3 对塑造 CD4+ 和 CD8+ T 细胞对特定病毒的整体反应的影响 LCMV 的表位。我们还将定义 Blimp1 和下游因子，包括 E-box 结合因子抑制剂 Id3。最后，我们将确定 Tim-3 胞质尾信号传导在调节 T 细胞中的作用激活、记忆和疲劳。