The Molecular Mechanism of Tim-3-mediated T Cell Dysfunction

Tim-3介导的T细胞功能障碍的分子机制

• 批准号: 8596323
• 负责人: Thomas Pertel
• 金额: $ 5.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596323
• 关键词: Address; Affinity Chromatography; Antigens; Autoimmune Diseases; Autoimmune Responses; Binding; Biology; CD28 gene; CD3 Antigens; CD8B1 gene; Cell Death; Cell physiology; Cells; Cessation of life; Chiroptera; Chronic; Communicable Diseases; Coupled; Cytoplasmic Tail; Data; Defect; Development; Disease Progression; Experimental Autoimmune Encephalomyelitis; Functional disorder; Galactose Binding Lectin; Gene Family; Generations; Genes; Genetic; HIV; HLA-B Antigens; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunosuppressive Agents; Incidence; Individual; Infection Control; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Knockout Mice; Laboratories; Ligands; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Molecular; Mucins; Multiple Sclerosis; Mus; Pathway interactions; Phenotype; Play; Psoriasis; Publishing; Regulation; Research; Resolution; Rheumatoid Arthritis; Role; Signal Transduction; T cell response; T-Cell Development; T-Lymphocyte; Tail; Transcript; Up-Regulation; Viral; Virus Diseases; Work; Yeasts; base; cytokine; exhaust; exhaustion; human disease; in vivo; member; mouse model; programs; public health relevance; response; yeast two hybrid system

DESCRIPTION (provided by applicant): We cloned Tim-3 as a molecule differentially expressed on IFN-gamma producing Th1/Tc1 cells and more recently found that Tim-3 is also expressed on pathogenic pro-inflammatory Th17 cells. We identified Galectin-9 as the Tim-3 ligand, and found that the interaction of galectin-9 with Tim-3 led to cell death and subsequent termination of Th1/Tc1 responses. These studies, together with other in vivo blockade studies with soluble Tim- 3, suggested that Tim-3 is inhibitory molecule necessary for dampening of effector Th1/Tc1 immunity. Exciting new data suggests that Tim-3 is also involved in inducing T cell exhaustion. Tim-3 expression is increased on effector T cells in chronic viral infections (e.g HIV) and cancers, rendering them dysfunctional, however in human autoimmune diseases there is loss of Tim-3 expression on effector T cells making them highly proinflammatory and pathogenic. Therefore, Tim-3 plays an important role in multiple human diseases, yet surprisingly little is known about the functional biology of Tim-3: it is not clear what induces Ti-3 expression on T cells and how it mediates its inhibitory effects. To understand the intracellular pathways that mediate Tim-3 function, we undertook a yeast two-hybrid screen and identified Bat3 (HLA-B associated transcript 3) as a molecule that binds to the Tim-3 cytoplasmic tail. Bat3, when bound to the Tim-3 tail, acts as a molecular "gate-keeper" that regulates Tim-3 inhibitory functions. To address this hypothesis we propose the following specific aim: 1) Identify molecular mechanisms by which Tim-3 signals into T cells to induce T cell dysfunction/exhaustion. Since we have identified Bat3 as a binding partner for the Tim-3 tail, we will analyze whether conditional loss of Bat-3 will induce T cell dysfunction and study how Bat3 bound to Tim-3 regulates proximal CD3-TcR signaling. The proposed studies will identify the molecular mechanisms by which Tim-3 mediates its inhibitory function in T cells that could be exploited to regulate autoimmune responses. While boosting Tim-3 signals could dampen autoimmune disease, repressing Tim-3 function could augment immune responses in chronic viral infections (e.g. HIV) and cancer.

描述（由申请人提供）：我们将 Tim-3 克隆为在产生 IFN-γ 的 Th1/Tc1 细胞上差异表达的分子，最近发现 Tim-3 也在致病性促炎 Th17 细胞上表达。我们将 Galectin-9 鉴定为 Tim-3 配体，并发现 Galectin-9 与 Tim-3 的相互作用导致细胞死亡并随后终止 Th1/Tc1 反应。这些研究与其他可溶性 Tim-3 体内阻断研究一起表明 Tim-3 是抑制效应 Th1/Tc1 免疫所必需的抑制分子。令人兴奋的新数据表明 Tim-3 也参与诱导 T 细胞耗竭。在慢性病毒感染（例如 HIV）和癌症中，效应 T 细胞上的 Tim-3 表达增加，导致其功能失调，但在人类自身免疫性疾病中，效应 T 细胞上的 Tim-3 表达缺失，使其具有高度促炎性和致病性。因此，Tim-3 在多种人类疾病中发挥着重要作用，但令人惊讶的是，人们对 Tim-3 的功能生物学知之甚少：尚不清楚是什么诱导 T 细胞上 Ti-3 的表达以及它如何介导其抑制作用。了解细胞内 为了了解介导 Tim-3 功能的途径，我们进行了酵母双杂交筛选，并鉴定了 Bat3（HLA-B 相关转录物 3）作为与 Tim-3 细胞质尾结合的分子。 Bat3 当与 Tim-3 尾部结合时，充当调节 Tim-3 抑制功能的分子“看门人”。为了解决这个假设，我们提出以下具体目标：1）确定 Tim-3 向 T 细胞发出信号以诱导 T 细胞功能障碍/耗竭的分子机制。由于我们已经确定 Bat3 是 Tim-3 尾部的结合伴侣，因此我们将分析 Bat-3 的条件性缺失是否会诱导 T 细胞功能障碍，并研究 Bat3 与 Tim-3 结合如何调节近端 CD3-TcR 信号传导。拟议的研究将确定 Tim-3 在 T 细胞中介导其抑制功能的分子机制，可用于调节自身免疫反应。虽然增强 Tim-3 信号可以抑制自身免疫性疾病，但抑制 Tim-3 功能可以增强慢性病毒感染（例如 HIV）和癌症的免疫反应。