Bacterial and Liposomal Antigen Processing

细菌和脂质体抗原处理

• 批准号: 7919824
• 负责人: Clifford V Harding
• 金额: $ 35.48万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919824
• 关键词: Address; Animal Model; Antigen-Presenting Cells; Antigens; Apoptosis; Applications Grants; Autophagocytosis; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell model; Cells; Containment; Cross Presentation; Cytosol; Dendritic Cells; Detection; Development; Disease; Dissection; Future; Generations; Genes; Grant; Host Defense; Human; Immune; Immune response; Immunotherapy; Infection; Interferon Type II; Interferons; Knockout Mice; Knowledge; Leishmania; Liposomes; Lung; Lymphoid; MHC Class I Genes; Modeling; Molecular; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Organ; Organism; Ovalbumin; Pathogenesis; Peptide Hydrolases; Peptides; Phagosomes; Play; Process; Production; Receptor Signaling; Regulation; Research; Respiratory physiology; Role; Salmonella; Site; System; T-Lymphocyte; Testing; Toll-like receptors; Toxoplasma; Tuberculosis; Vaccine Design; Vaccines; antigen processing; cell type; cytokine; design; fighting; interferon-alpha B; lymph nodes; macrophage; meetings; microbicide; multicatalytic endopeptidase complex; p97 ATPase; pathogen; pathogenic bacteria; response

DESCRIPTION (provided by applicant): Class I MHC Ag cross processing allows exogenous or vacuolar Ags to be processed for presentation to CD8+ T cells. Cross processing is essential for priming of CD8+ naive T cells by dendritic cells (DCs) in lymph nodes. A less recognized but potentially critical role of cross processing is to allow cells in non-lymphoid organs that are infected with vacuolar pathogens, e.g. Mycobacterium tuberculosis (MTB), to present pathogen-derived antigens to CD8+ effector T cells to elicit cytokine production or cytolytic function. DCs and macrophages may both harbor MTB and may hypothetically present MTB Ags to CD8+ effector T cells, allowing CD8+ T cells to contribute to containment of MTB infection. Research direction: This grant is to study basic mechanisms of bacterial Ag processing with a primary focus on MHC-I cross processing. MTB is selected as a model organism that represents an excellent model for processing of intravacuolar pathogens in addition to its significance as a human pathogen. Questions to be solved: We do not know which MTB-infected APCs have cross processing function; this has important implications for generation of immune responses vs. immune evasion. We do not understand mechanisms for cross processing of vacuolar pathogens, e.g. MTB, and cross processing functions of physiologically important lung APCs have not been investigated. Hypothesis: Cross processing of vacuolar organisms (e.g. MTB) allows recognition of infected cells by CD8+ T cells, contributing to host defense. DCs and macrophages may both cross present Ags to effector T cells, although they may use different cross processing mechanisms, undergo different regulation by pathogens, and play different roles in immune responses. Aim 1 addresses basic mechanisms of cross processing of MTB. Aim 2 investigates the cross processing functions of lung APCs. Aim 3 addresses regulation of cross processing by Toll-like receptors, interferons and MTB. Significance in lay terms: These studies will discover mechanisms that allow immune recognition of the causative agent of tuberculosis by CD8+ T cells, which help fight tuberculosis infection. This will increase our understanding of tuberculosis pathogenesis and aid development of strategies for enhanced vaccine design or immunotherapy for tuberculosis and other diseases.

描述（由申请人提供）：I类MHC抗原交叉加工允许外源性或液泡抗原被加工以提呈给CD 8 + T细胞。交叉处理对于淋巴结中树突状细胞（DC）引发CD 8+初始T细胞是必不可少的。交叉处理的一个不太被认识到但可能至关重要的作用是允许被空泡病原体（例如结核分枝杆菌（MTB））感染的非淋巴器官中的细胞将病原体衍生的抗原呈递给CD 8+效应T细胞以引发细胞因子产生或细胞溶解功能。DC和巨噬细胞都可以携带MTB，并且可以假设将MTB Ag呈递给CD 8+效应T细胞，从而允许CD 8 + T细胞有助于遏制MTB感染。研究方向：该基金将研究细菌Ag加工的基本机制，主要关注MHC-I交叉加工。选择MTB作为模式生物，其除了作为人类病原体的重要性之外，还代表了用于处理液泡内病原体的优良模型。待解决的问题：我们不知道哪些MTB感染的APC具有交叉处理功能;这对免疫应答的产生与免疫逃避具有重要意义。我们不了解空泡病原体（例如MTB）的交叉处理机制，并且尚未研究生理学上重要的肺APC的交叉处理功能。假设：液泡生物（例如MTB）的交叉加工允许CD 8 + T细胞识别受感染的细胞，有助于宿主防御。DC和巨噬细胞都可以交叉提呈Ags给效应T细胞，尽管它们可能使用不同的交叉处理机制，受到病原体的不同调节，并且在免疫应答中发挥不同的作用。目标1阐述了结核分枝杆菌交叉加工的基本机制。目的2研究肺APC的交叉处理功能。目的3解决了Toll样受体、干扰素和MTB对交叉处理的调节。通俗意义：这些研究将发现允许CD 8 + T细胞免疫识别结核病病原体的机制，这有助于对抗结核病感染。这将增加我们对结核病发病机制的理解，并有助于制定针对结核病和其他疾病的增强疫苗设计或免疫疗法的策略。