Class II MHC Transport and Function

II 类 MHC 运输和功能

基本信息

批准号：
7750609
负责人：
Clifford V Harding
金额：
$ 36.42万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750609
关键词：
Acute Acylation Adjuvant Aerosols Affinity Agonist Amino Acid Sequence Antigen Presentation Pathway Antigens Area Automobile Driving Bacillus (bacterium)Binding CD4 Positive T Lymphocytes Cell Maturation Cells Chronic Collaborations Data Dendritic Cells Dependence Dissection Distal Down-Regulation Engineering Epigenetic Process Funding Gene Expression Gene Proteins Generations Genes Genetic Genetic Transcription Genus Mycobacterium Goals Grant Histone Acetylation Histones Host Defense Host resistance Human Immune Immune response Immunologic Surveillance Infection Inflammatory Interferon Type II Investigation Knock-out Lead Limb structure Lipids Lipoproteins MHC Class II Genes Modeling Molecular Mus Mutate Mycobacterium tuberculosis Natural Immunity Organism Pathogenesis Pattern Peptide Sequence Determination Phagosomes Phase Process Production Property Proteins Receptor Signaling Recombinants Regulation Relative (related person)Reporting Research Role Signal Transduction Structural Protein Structure Structure-Activity Relationship T cell response T-Lymphocyte TLR1 gene TLR2 gene TLR6 gene Testing Th1/Th2 Differentiation Pathway Toll-like receptors Tuberculosis Vaccines Variant adaptive immunity antimicrobial cell type chromatin remodeling cytokine immune function in vivo in vivo Model macrophage mouse model novel pathogen receptor response

项目摘要

Our goal is to study how infection with Mycobacterium tuberculosis (MTB) regulates antigen (Ag) presenting cells (APCs, e.g.macrophages and dendritic cells). MTB is an important human pathogen that evades host defenses to maintain chronic infection. Dendritic cells must present MTB Ags to prime CD4 T cell responses, and CD4 effector T cells must recognize infected macrophages presenting MTB Ags to provide effector functions, including production of IFN-g, which is essential to host resistance. Regulation of macrophage ARC function by MTB is important to tuberculosis pathogenesis but remains poorly understood. We propose that Toll-like receptor (TLR) signaling by MTB pathogen-associated molecular patterns (PAMPs) produces both immune- activating effects (e.g.induction of pro-inflammatory cytokines by macrophages or maturation of dendritic cells) and late phase downregulatory effects (e.g.inhibition of MHC-II expression and Ag processing by macrophages that are chronically infected with MTB). We will investigate the ability of MTB PAMPs to signal via TLRs to modulate dendritic cell and macrophage APC function. We will focus on three major lipoprotein PAMPs of MTB that were identified in our previous studies, namely LpqH (19-kDa lipoprotein), LprG and LprA. We will study the ability of LpqH, LprG and LprA to signal via TLR2, TLR2/1 or TLR2/6, induce macrophage expression of pro-inflammatory cytokines, act as adjuvants to influence Th1/Th2 differentiation of T cell responses, promote dendritic cell maturation and cause late phase downregulation of macrophage MHC-II expression and Ag processing (including signaling and chromatin remodeling studies). Approaches will include production of recombinant His-tagged PAMPs and engineered variants for structure-function studies, generation of PAMP knockout MTB and M. bovis BCG and investigation of APC regulation by RFP-tagged mycobacteria in vivo with a mouse model of tuberculosis. Overall, these studies will enhance our understanding of tuberculosis pathogenesis and contribute to optimization of vaccine strategies for tuberculosis.

我们的目标是研究结核分枝杆菌 (MTB) 感染如何调节抗原 (Ag) 呈递细胞（APC，例如巨噬细胞和树突状细胞）。 MTB 是一个重要的人类逃避宿主防御以维持慢性感染的病原体。树突状细胞必须存在 MTB 抗原启动 CD4 T 细胞反应，CD4 效应 T 细胞必须识别感染巨噬细胞呈递 MTB Ag 以提供效应子功能，包括产生 IFN-g，这对于宿主的抵抗力至关重要。 MTB 对巨噬细胞 ARC 功能的调节很重要结核病的发病机制，但仍知之甚少。我们提出Toll样受体 MTB 病原体相关分子模式 (PAMP) 的 (TLR) 信号传导产生免疫- 激活作用（例如巨噬细胞诱导促炎细胞因子或成熟树突状细胞）和晚期下调效应（例如 MHC-II 表达和 Ag 的抑制）由长期感染 MTB 的巨噬细胞进行处理）。我们将研究 MTB PAMP 通过 TLR 发出信号来调节树突状细胞和巨噬细胞APC功能。我们将重点关注 MTB 的三种主要脂蛋白 PAMP，它们是我们之前的研究中鉴定出了 LpqH（19-kDa 脂蛋白）、LprG 和 LprA。我们将学习 LpqH、LprG 和 LprA 通过 TLR2、TLR2/1 或 TLR2/6 发出信号、诱导巨噬细胞的能力促炎细胞因子的表达，作为佐剂影响 T 细胞的 Th1/Th2 分化细胞反应，促进树突状细胞成熟并导致晚期下调巨噬细胞 MHC-II 表达和 Ag 加工（包括信号传导和染色质重塑研究）。方法包括生产重组组氨酸标签的 PAMP 和工程化的用于结构功能研究的变体、PAMP 敲除 MTB 和牛分枝杆菌 BCG 的生成以及使用小鼠模型研究 RFP 标记的分枝杆菌体内 APC 调节结核。总的来说，这些研究将增强我们对结核病发病机制的了解并有助于优化结核病疫苗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interferon-gamma differentially regulates antigen-processing functions in distinct endocytic compartments of macrophages with constitutive expression of class II major histocompatibility complex molecules.

干扰素-γ 差异性地调节巨噬细胞不同内吞区室中的抗原加工功能，并组成型表达 II 类主要组织相容性复合物分子。

DOI：
10.1046/j.1365-2567.1996.d01-632.x
发表时间：
1996
期刊：
Immunology
影响因子：
6.4
作者：
Hockett,RD;Cook,JR;Findlay,K;Harding,CV
通讯作者：
Harding,CV

B lymphocytes secrete antigen-presenting vesicles.

DOI：
10.1084/jem.183.3.1161
发表时间：
1996-03-01
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Raposo G;Nijman HW;Stoorvogel W;Liejendekker R;Harding CV;Melief CJ;Geuze HJ
通讯作者：
Geuze HJ

P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1.

P2X7 受体刺激的含 MHC II 类外泌体的分泌需要 ASC/NLRP3 炎性体，但不依赖于 caspase-1。