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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：
10333307
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/10333307
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.

项目概要我们将 TIM 3 克隆为在产生 IFN-g 的 T 细胞上差异表达的分子，并已成为主要的终止效应 T 细胞反应所必需的抑制分子。 Tim 3 表达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。相比之下，在人类自身免疫性疾病中，效应 T 细胞上 Tim 3 表达缺失，使其高度亲炎症性和致病性。由于其在 T 细胞耗竭中的作用，Tim 3 正在成为多个临床研究的目标癌症试验。 Tim 3 也在树突状细胞 (DC) 上组成型表达，然而，其作用和功能 Tim 3 对 DC 的作用尚不清楚，从临床试验的角度来看，理解这一点尤其重要抗 Tim 3 抗体正在进行中。与 T 细胞一样，Tim 3 在 DC 中与其接头蛋白 Bat-3 共表达，其中 Bat-3 充当分子“门 keeper”，限制 Tim 3 信号传导和功能。为了了解 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“敲除”小鼠。初步研究表明，不受限制在没有 Bat-3 的情况下，Tim 3 的信号传导使 Bat-3 缺陷的 DC 产生耐受性，使得它们不能有效地发挥作用。诱导炎症 T 细胞反应，并且小鼠能够抵抗自身免疫的发展。基于我们的根据初步数据，我们假设 DC 中未减弱的 Tim 3 信号传导促进了耐受性 DC 的产生。为了解决这个假设，我们提出两个具体目标： 1. 确定 Tim 3/Bat-3 相互作用如何调节耐受性 DC 的发育。我们观察到通过删除 Bat-3，Tim 3 的无阻碍信号传导（特别是在 DC 中）抑制了多种细胞的发育自身免疫性疾病，包括重点关注的实验性自身免疫性脑脊髓炎（EAE）的这项建议。在 DC 中使用 Tim 3 和 Bat-3 的条件“敲除”小鼠，我们建议确定 Bat-3 cKO 小鼠对自身免疫的抵抗是否部分或完全恢复从同一组 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 DC 表型和功能。 2.确定Tim 3与Smad/TGF-b通路相互作用的分子机制促进耐受性 DC 的产生。使用无偏见的蛋白质组筛选来识别分子在没有 Bat-3 的情况下与 Tim 3 尾结合，我们鉴定出 Smad-2，TGF-b 途径的转导子，作为 Tim 3 相互作用蛋白。这一新颖的观察使我们能够研究 Tim 3 的机制介导其抑制功能，具体来说，我们将能够确定蒂姆的分子基础 3/Smad/TGF-b 途径促进耐受性 DC 的发育。使用高密度时间 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 通路通过该网络介导其在 DC 中的抑制功能。拟议的研究将确定 Tim 3:Bat-3 通路如何使 DC 产生耐受性，从而提供关键的可以利用这些信息来有益于多种人类疾病。虽然抑制 Tim 3 功能可以增强慢性病毒感染和癌症的免疫反应，增强 Tim 3 信号可能抑制自身免疫性疾病并促进抗原特异性耐受。