Roles for Exosomes in Adaptive Immunity to M. tuberculosis

外泌体在结核分枝杆菌适应性免疫中的作用

基本信息

批准号：
8426877
负责人：
Pamela A Wearsch
金额：
$ 19.77万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8426877
关键词：
Address Agonist Antibiotic Resistance Antigen Presentation Antigen-Presenting Cells Antigens Area Attention B-Lymphocytes Bacterial Infections Biochemical Biogenesis Biological Blood Bronchoalveolar Lavage CD4 Positive T Lymphocytes CD8B1 gene Cause of Death Cell membrane Cells Characteristics Communicable Diseases Complex Containment Cross-Priming Dendritic Cells Development Diagnosis Diagnostic Disease model Endocytic Vesicle Foundations Future Generations Genus Mycobacterium Histocompatibility Antigens Class II Immune response Immune system Immunity Immunologic Receptors In Vitro Infection Inflammatory Inflammatory Response Inherited Investigation Lead Ligands Liquid substance Literature Lung Malignant Neoplasms Mediating Membrane Membrane Proteins Modeling Molecular Multivesicular Body Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Natural Immunity Pattern Peptide/MHC Complex Physiological Population Prevention strategy Production Property Regulation Relative (related person)Role Signal Pathway Signal Transduction Site Sorting - Cell Movement System T cell response T-Cell Activation T-Lymphocyte TCR Activation TLR2 gene TLR4 gene Testing Therapeutic Tuberculosis Tumor-Derived Urine Vaccines Vesicle adaptive immunity base cell type cytokine in vivo insight intercellular communication macrophage mouse model novel novel diagnostics novel therapeutics pathogen public health relevance response tool tuberculosis treatment tumor immunology

项目摘要

DESCRIPTION (provided by applicant): Exosomes are small vesicles of endocytic origin that are released from a variety of cell types under normal or pathological conditions. Although originally described in the 1980's, these vesicles have recently garnered significant attention for their ability to stimulate innate and adaptive immune responses in vitro. In this proposal we predict that exosomes serve a unique role in host responses to Mycobacterium tuberculosis (Mtb) infection. Our main hypothesis is that infected dendritic cells (DCs) and macrophages respond to Mtb-infection by releasing exosomes rich in Mtb antigens and PAMPs, thereby broadcasting stimulation of both innate and adaptive immune receptors beyond the site of infection to enhance immunity to Mtb. The overall objective of this proposal is to determine the biochemical and functional characteristics of exosomes released in response to Mtb-infection. In particular, we will focus on CD4+ T cell responses to exosomes since they are poorly characterized in infection models and may be important for the containment of Mtb-infection. We predict that exosomes provide two signals to promote the genesis of protective CD4+ T cell responses to Mtb. 1. Antigenic signal: Exosomes either directly present peptide-MHC-II complexes to T cells or transfer peptide-MHC-II complexes to recipient DCs for antigen presentation. 2. TLR signaling: CD4+ T cells express TLR2 and respond to TLR2 agonists with enhanced proliferative and cytokine responses upon TCR stimulation. We therefore propose that Mtb TLR2 ligands contained within exosomes generate a second signal during antigen presentation to amplify TCR activation. To assess this model, will first evaluate the biogenesis, composition, and MHC class II antigen presentation capacities of exosomes released by infected DCs and macrophages (Aims 1 and 2). We will then evaluate the ability of TLR2 agonists in Mtb-exosomes to stimulate TLR2 on T cells and enhance T cell responses to Mtb antigens (Aim 3). These studies will test a highly novel function for exosomes in the co-stimulation of T cells responses via T cell-expressed TLRs and will advance our limited understanding of exosome functions in adaptive immunity to Mtb. These studies may also serve as a foundation for the future development of exosome-based diagnostics and therapeutics.

描述（由申请人提供）：外泌体是内吞来源的小囊泡，在正常或病理条件下从多种细胞类型中释放。尽管最初是在 20 世纪 80 年代描述的，但这些囊泡最近引起了人们的广泛关注它们在体外刺激先天性和适应性免疫反应的能力。在该提案中，我们预测外泌体在宿主对结核分枝杆菌（Mtb）感染的反应中发挥独特的作用。我们的主要假设是，受感染的树突状细胞（DC）和巨噬细胞通过释放富含Mtb抗原和PAMP的外泌体来响应Mtb感染，从而将先天性和适应性免疫受体的刺激传播到感染部位之外，以增强对Mtb的免疫力。该提案的总体目标是确定响应结核分枝杆菌感染而释放的外泌体的生化和功能特征。特别是，我们将重点关注 CD4+ T 细胞对外泌体的反应，因为它们在感染模型中的特征很差，但可能对于遏制 Mtb 感染很重要。我们预测外泌体提供两个信号来促进保护性 CD4+ T 细胞对 Mtb 反应的发生。 1.抗原信号：外泌体要么直接将肽-MHC-II复合物呈递给T细胞，要么将肽-MHC-II复合物转移至受体DC以进行抗原呈递。 2. TLR信号传导：CD4+T细胞表达TLR2并响应TLR2激动剂，在TCR刺激后增强增殖和细胞因子反应。因此，我们提出，外泌体中包含的 Mtb TLR2 配体在抗原呈递过程中产生第二个信号，以放大 TCR 激活。为了评估该模型，将首先评估受感染的 DC 和巨噬细胞释放的外泌体的生物发生、组成和 MHC II 类抗原呈递能力（目标 1 和 2）。然后，我们将评估 Mtb 外泌体中的 TLR2 激动剂刺激 T 细胞上的 TLR2 并增强 T 细胞对 Mtb 抗原的反应的能力（目标 3）。这些研究将测试外泌体在通过 T 细胞表达的 TLR 共同刺激 T 细胞反应中的一种高度新颖的功能，并将增进我们对外泌体在 Mtb 适应性免疫中功能的有限了解。这些研究也可以作为未来开发基于外泌体的诊断和治疗的基础。