Class II MHC Transport and Function

II 类 MHC 运输和功能

• 批准号: 7161727
• 负责人: Clifford V Harding
• 金额: $ 37.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161727
• 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; Calmette-Guerin Bacillus; 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; Immunity; 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; Purpose; Receptor Signaling; Recombinants; Regulation; Relative (related person); Reporting; Research; Role; Signal Transduction; Structural Protein; Structure; Structure-Activity Relationship; T-Lymphocyte; TLR1 gene; TLR2 gene; TLR6 gene; Testing; Th1/Th2 Differentiation Pathway; Toll-like receptors; Tuberculosis; Vaccines; Variant; antimicrobial; cell type; chromatin remodeling; cytokine; immune function; in vivo; in vivo Model; macrophage; mouse model; novel; pathogen; receptor; response

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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 是一种重要的人类病原体，它可以逃避宿主防御以维持慢性感染。树突状细胞必须呈递 MTB Ag 以引发 CD4 T 细胞反应，CD4 效应 T 细胞必须识别呈递 MTB Ag 的受感染巨噬细胞以提供效应功能，包括产生 IFN-g，这对于宿主抵抗力至关重要。 MTB 对巨噬细胞 ARC 功能的调节对于结核病发病机制很重要，但人们对此仍知之甚少。我们认为，MTB 病原体相关分子模式 (PAMP) 的 Toll 样受体 (TLR) 信号传导既产生免疫激活效应（例如，巨噬细胞诱导促炎细胞因子或树突状细胞成熟），也产生后期下调效应（例如抑制 MHC-II 表达和慢性感染 MTB 的巨噬细胞处理 Ag）。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 功能的能力。我们将重点关注在我们之前的研究中鉴定出的 MTB 的三种主要脂蛋白 PAMP，即 LpqH（19-kDa 脂蛋白）、LprG 和 LprA。我们将研究LpqH、LprG和LprA通过TLR2、TLR2/1或TLR2/6发出信号的能力，诱导巨噬细胞表达促炎细胞因子，作为佐剂影响T细胞反应的Th1/Th2分化，促进树突状细胞成熟并导致巨噬细胞 MHC-II 表达和 Ag 加工的晚期下调（包括信号传导和染色质重塑研究）。方法包括生产重组 His 标记的 PAMP 和用于结构功能研究的工程变体、生成 PAMP 敲除 MTB 和牛分枝杆菌 BCG，以及利用结核病小鼠模型研究体内 RFP 标记的分枝杆菌对 APC 的调节。总体而言，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。