Role of Tim-3:Bat-3 pathway in inducing tolerogenic DCs and peripheral tolerance

Tim-3:Bat-3 通路在诱导耐受性 DC 和外周耐受中的作用

基本信息

批准号：
10094188
负责人：
VIJAY K. KUCHROO
金额：
$ 43.49万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094188
关键词：
Adaptor Signaling Protein Address Affect Antibodies Antigens Autoimmune Diseases Autoimmunity Binding Biochemical CD8B1 gene Cell physiology Cell surface Cells Cellular biology Chiroptera Chronic Clinical Clinical Trials Communicable Diseases Data Dendritic Cells Development Experimental Autoimmune Encephalomyelitis Functional disorder Gatekeeping Gene Family Generations Genes Genetic Transcription Glutamates Human ITGAX gene Immune response Immunoglobulins Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interferon Type II Knockout Mice Laboratories Macrophage Activation Malignant Neoplasms Mediating Molecular Mucins Multiple Sclerosis Mus Myelogenous Myeloid Cells Pathogenicity Pathologic Pathway interactions Phenotype Play Population Predisposition Proteins Proteomics Psoriasis Reporting Resistance Rheumatoid Arthritis Role Series Severities Signal Transduction Signaling Molecule T cell response T-Cell Development T-Lymphocyte TC1 Cell Tail Therapeutic Tissues Transducers Transforming Growth Factor beta Tyrosine Viral Viral Cancer Virus Diseases base cancer clinical trial conditional knockout cytokine density differential expression effector T cell exhaust exhaustion experimental study human disease immunoregulation in vivo macrophage member novel overexpression peripheral tolerance

项目摘要

PROJECT SUMMARY We cloned TIM 3 as a molecule differentially expressed on IFN-g producing T cells and has emerged as a major inhibitory molecule necessary for the termination of effector T cell responses. Tim 3 expression is increased on effector T cells in human chronic viral infections and cancers, rendering them dysfunctional. In contrast, in human autoimmune diseases, there is loss of Tim 3 expression on effector T cells, rendering them highly pro- inflammatory and pathogenic. Because of its role in T cell exhaustion, Tim 3 is being targeted in multiple clinical trials for cancer. Tim 3 is also expressed constitutively on dendritic cells (DCs), however, the role and function of Tim 3 on DCs is not well understood and this is especially important to understand, in the view of clinical trials that are underway with anti-Tim 3 antibodies. As in T cells, Tim 3 is co-expressed in DCs with its adapter protein Bat-3, where Bat-3 acts as a molecular “gate- keeper”, that restricts Tim 3 signaling and function. To understand the function of Tim 3 in DCs, we have generated conditional “knock-out” mice of both Tim 3 and Bat-3 in DCs. Initial studies indicate that unrestricted signaling of Tim 3 in the absence of Bat-3, makes Bat-3-deficient DCs tolerogenic such that they do not effectively induce inflammatory T cell responses and the mice are resistant to development of autoimmunity. Based on our preliminary data, we hypothesize that unabated Tim 3 signaling in DCs promotes generation of tolerogenic DCs. To address this hypothesis, we propose two specific aims: 1. Determine how the Tim 3/Bat-3 interaction regulates development of tolerogenic DCs. We have observed that unopposed signaling of Tim 3, by deleting Bat-3, specifically in DCs inhibits development of multiple autoimmune diseases including Experimental Autoimmune Encephalomyelitis (EAE) which is the focus of this proposal. Using conditional “knock-out” mice for both Tim 3 and Bat-3 in DCs, we propose to determine whether resistance to autoimmunity in Bat-3 cKO mice is partly or completely restored by deletion of Tim 3 from the same set of DCs. Furthermore, this will also allow us to determine how loss of Bat-3 regulates DC phenotype and function. 2. Determine the molecular mechanism by which interaction of Tim 3 and the Smad/TGF-b pathway promotes the generation of tolerogenic DCs. Using an unbiased proteomic screen to identify molecules that bind to the Tim 3 tail in the absence of Bat-3, we identified Smad-2, a transducer of TGF-b pathway, as a Tim 3 interacting protein. This novel observation allows us to study the mechanism by which Tim 3 mediates its inhibitory function, specifically we will be able to determine the molecular basis by which Tim 3/Smad/TGF-b pathway promotes the development of tolerogenic DCs. Using high density temporal transcriptional analysis of the Tim 3 and Bat-3 deficient DCs, we propose to develop transcriptional networks by which the Tim 3:Bat-3 pathway mediates its inhibitory function in DCs. The proposed studies will identify how the Tim 3:Bat-3 pathway makes DCs tolerogenic, providing critical information that could be exploited to benefit multiple human diseases. While repressing Tim 3 function could augment immune responses in chronic viral infections and cancer, boosting Tim 3 signals could dampen autoimmune diseases and promote antigen specific tolerance.

项目摘要我们将TIM 3克隆为在IFN-G产生T细胞上差异表达的分子，并已成为主要终止效应T细胞反应所需的抑制分子。 TIM 3表达在上面增加人类慢性病毒感染和癌症中的效应T细胞，使其功能失调。相反，人类自身免疫性疾病，效应T细胞上TIM 3表达丧失，使其高度促进炎症和致病性。由于其在T细胞耗尽中的作用，TIM 3是针对多个临床的。癌症试验。 TIM 3在树突状细胞（DC）上也始终表达，但是，角色和功能临床试验的观点，DC上的Tim 3上的第3章尚未充分理解，这对于理解尤其重要抗TIM 3抗体正在进行。与T细胞一样，TIM 3与其衔接蛋白BAT-3共表达，其中BAT-3充当分子“栅极” 守护者”，这限制了tim 3的信号和功能。要了解tim 3在DC中的功能，我们有在DC中产生了TIM 3和BAT-3的条件“淘汰”小鼠。初步研究表明无限制在没有BAT-3的情况下，TIM 3的信号传导使BAT-3缺陷DC耐受性，以至于它们没有有效地诱导炎症性T细胞反应，小鼠对自身免疫的发展有抵抗力。基于我们初步数据，我们假设DC中的不减弱的TIM 3信号促进了耐受性DC的产生。为了解决这一假设，我们提出了两个具体目标： 1。确定TIM 3/BAT-3相互作用如何调节耐受性DC的发展。我们已经观察到通过删除BAT-3，尤其是在DC中，TIM 3的无反对信号传导抑制了多个的发展自身免疫性疾病，包括实验性自身免疫性脑脊髓炎（EAE），这是重点该提议。在DC中使用有条件的“淘汰”小鼠，我们建议确定在BAT-3 CKO小鼠中对自身免疫性的抵抗力是部分还是完全恢复从同一组DC中删除TIM 3。此外，这也将使我们能够确定如何损失 BAT-3调节直流表型和功能。 2。确定TIM 3和SMAD/TGF-B途径的相互作用的分子机制促进耐受性DC的产生。使用公正的蛋白质组学筛选来识别分子在没有BAT-3的情况下，与TIM 3尾巴结合，我们确定了TGF-B途径的传感器Smad-2，作为TIM 3相互作用的蛋白质。这种新颖的观察使我们能够研究Tim 3的机制介导其抑制功能，特别是我们能够确定tim的分子基础 3/SMAD/TGF-B途径促进了耐受性DC的发展。使用高密度临时 TIM 3和BAT-3缺陷DC的转录分析，我们建议开发转录 TIM 3：BAT-3途径在DC中介导其抑制功能的网络。拟议的研究将确定TIM 3：BAT-3途径如何使DCS耐受性，从而提供关键可以探索以使多种人类疾病受益的信息。在反映tim 3功能时可以增强慢性病毒感染和癌症中的免疫回应，提高蒂姆3信号可以跳舞自身免疫性疾病并促进抗原特异性耐受性。