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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.

项目总结