Antigen processing and the age-related decline in protection against influenza

抗原加工和与年龄相关的流感防护能力下降

• 批准号: 7671432
• 负责人: Tara Robinson
• 金额: $ 4.33万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671432
• 关键词: Affect; Age; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated Vaccines; B-Lymphocytes; Binding; Biological Process; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cytosol; Dendritic Cells; Development; Digestion; Elderly; Endoplasmic Reticulum; Engineering; Epitopes; Glycoproteins; Goals; Histocompatibility Antigens Class II; Human; Immune response; Immune system; Infection; Infectious Agent; Influenza; Investigation; Lead; Left; Longevity; Major Histocompatibility Complex; Modeling; Mus; Organism; Pathway interactions; Peptide Transport; Peptides; Population; Process; Production; Proteins; Proteolysis; Public Health; Publishing; Relative (related person); Reporting; Research; Shapes; Solutions; T-Cell Activation; T-Lymphocyte; Testing; Thinking; United States; Vaccination; Vaccine Design; Vaccines; Vaccinia; Vaccinia virus; Varicellovirus; Viral; Virus Diseases; age related; aged; aging population; antigen processing; design; immunosenescence; improved; influenza virus vaccine; insight; killings; late endosome; macrophage; mouse model; multicatalytic endopeptidase complex; novel; research study; response

DESCRIPTION (provided by applicant): Immune responses decline with age, leaving the elderly more susceptible to infections such as influenza. B cell responses are correlated with a protective immune response in humans, and robust antibody responses are generally dependent on a strong CD4+ T cell response. In turn, CD4+ T lymphocytes are activated by foreign peptides presented in the context of major histocompatibility complex (MHC) class II molecules. The conversion of whole antigen to MHC-bound peptide is termed antigen processing. In the conventional model, class ll-binding peptides are generated in the late endosome via unfolding and/or proteolysis and subsequently loaded onto class II molecules with the assistance of the H-2M heterodimer. In contrast, the conventional pathway for MHC class l-restricted presentation to CD8+ T cells entails delivery of antigen to the cytosol where it is digested by the proteasome. The resultant peptides are transported to the endoplasmic reticulum by the TAP heterodimer where they are loaded onto empty, nascent class I molecules. This dichotomy has strongly influenced thinking in the field for many years. Recently we reported on two MHC class ll-restricted influenza epitopes that are presented via a pathway that is decidedly class I-like in that presentation depends upon cytosolic delivery, functional proteasome and the presence of TAP. Analysis of bulk class ll-restricted responses against influenza and vaccinia revealed that a substantial proportion is directed against proteasome-dependent epitopes. We have designed a research plan, a natural extension of our published studies, in order to 1) assess the degree to which proteasome-dependent CD4+ T cells contribute to the immune response and protection from viral challenge, and 2) understand how age-related changes in antigen processing pathways and subsequent CD4+ T cell activation contribute to the decreased immune responses in the elderly. Execution of the plan could lead to new insights on CD4 T cell priming, and provide novel mechanisms to improve influenza vaccine design for the elderly. Influenza is a significant public health problem in the United States, despite attempts to protect the population with yearly vaccination. As we age our immune systems become increasingly unable to protect us from infections, and viruses such as influenza become a major concern. The current vaccine for influenza is not an acceptable solution because the elderly respond poorly to it, and it often provides incomplete protection. The experiments we propose probe basic aspects of the immune response that may point to ways of increasing vaccine potency, a development that would be particularly beneficial to the elderly.

描述（由申请人提供）：免疫反应随着年龄的增长而下降，使老年人更容易感染流感等感染。在人体中，B细胞应答与保护性免疫应答相关，而强大的抗体应答通常依赖于强大的CD4+ T细胞应答。反过来，CD4+ T淋巴细胞被主要组织相容性复合体（MHC） II类分子中的外源肽激活。将整个抗原转化为mhc结合肽的过程称为抗原加工。在传统模型中，II类结合肽通过展开和/或蛋白水解在核内体后期产生，随后在H-2M异源二聚体的帮助下装载到II类分子上。相比之下，MHC l类限制性呈递CD8+ T细胞的传统途径需要将抗原递送到细胞质中，在那里抗原被蛋白酶体消化。合成的肽通过TAP异源二聚体运输到内质网，在那里它们被装载到空的新生I类分子上。这种二分法多年来一直强烈地影响着该领域的思维。最近，我们报道了两种MHCⅱ类限制性流感表位，它们通过一种明确的ⅰ类途径呈递，这种呈递依赖于细胞质递送、功能性蛋白酶体和TAP的存在。对流感和牛痘的大量限制性应答的分析显示，相当大比例的应答是针对蛋白酶体依赖性表位的。我们设计了一项研究计划，这是我们已发表研究的自然延伸，目的是：1)评估蛋白酶体依赖性CD4+ T细胞对免疫反应和病毒攻击保护的贡献程度；2)了解抗原加工途径的年龄相关变化和随后的CD4+ T细胞激活如何导致老年人免疫反应下降。该计划的实施可能导致对CD4 T细胞启动的新见解，并为改进老年人流感疫苗设计提供新机制。在美国，流感是一个重大的公共卫生问题，尽管人们试图通过每年接种疫苗来保护民众。随着年龄的增长，我们的免疫系统越来越无法保护我们免受感染，而流感等病毒就成了一个主要问题。目前的流感疫苗不是一种可接受的解决方案，因为老年人对它的反应很差，而且它往往提供不完全的保护。我们提出的实验探讨了免疫反应的基本方面，可能会指出提高疫苗效力的方法，这一发展对老年人尤其有益。