Class II MHC Transport and Function

II 类 MHC 运输和功能

• 批准号: 7323239
• 负责人: Clifford V Harding
• 金额: $ 36.79万
• 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/7323239
• 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; 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

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）的感染如何调节抗原（AG） 呈现细胞（APC，例如巨噬细胞和树突状细胞）。 MTB是重要的人 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 AGS对基本CD4 T细胞反应，CD4效应T细胞必须识别感染 出现MTB AGS以提供效应子功能的巨噬细胞，包括IFN-G的产生， 这对于托管阻力至关重要。 MTB对巨噬细胞弧功能的调节很重要 结核病的发病机理，但仍然很少了解。我们提出类似Toll的受体 （TLR）通过MTB病原体相关的分子模式（PAMP）信号传导，两者都会产生免疫 激活作用（例如，巨噬细胞诱导促炎性细胞因子或成熟 树突状细胞）和晚期下调作用（例如，抑制MHC-II表达和Ag 由巨噬细胞的加工，巨噬细胞长期感染了MTB）。 我们将研究MTB弹药通过TLR发出信号的能力，以调节树突状细胞和 巨噬细胞APC功能。我们将重点关注MTB的三个主要脂蛋白PAMP 在我们以前的研究中鉴定出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发出信号的能力，诱导巨噬细胞 促炎细胞因子的表达，充当影响T的Th1/Th2分化T的佐剂 细胞反应，促进树突状细胞的成熟并导致后期下调 巨噬细胞MHC-II表达和AG加工（包括信号和染色质重塑 研究）。方法将包括生产重组的His标记的助手和工程 用于结构功能研究的变体，pAMP基因敲除MTB和M. Bovis BCG和 用RFP标记的分枝杆菌在体内对APC调节的调节，并使用小鼠模型 结核。总体而言，这些研究将增强我们对结核病发病机理的理解 并有助于优化结核病策略。