MHC-Ib restricted T cell responses against Listeria monocytogenes

MHC-Ib 限制 T 细胞对单核细胞增生李斯特菌的反应

• 批准号: 7873036
• 负责人: SARAH E. F. D'ORAZIO
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873036
• 关键词: Antigenic Specificity; Antigens; Attention; Bacteria; Bacterial Infections; Binding; Blood typing procedure; CD8B1 gene; Categories; Cell Line; Cell surface; Cells; Chlamydia; Chlamydia trachomatis; Disease Outbreaks; Event; Genes; Genetic Polymorphism; Genus Mycobacterium; Haplotypes; Harvest; Human; Immune; Immune response; Immunity; Incidence; Individual; Infection; Lead; Lipids; Listeria monocytogenes; Mediating; Mediator of activation protein; Memory; Modeling; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Organism; Peptides; Play; Population; Proliferating; Proteins; Qa-1 Antigen; Reporting; Role; Salmonella; Splenocyte; Surface; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Time; Vaccine Design; Variant; adaptive immunity; antigen binding; design; foodborne; foodborne illness; macrophage; mortality; mouse model; novel; novel therapeutics; pathogen; public health relevance; research study; response

DESCRIPTION (provided by applicant): 1 Listeria monocytogenes (Lm) is a category B priority pathogen that causes outbreaks of 2 foodborne illness with a high incidence of morbidity and mortality. To achieve sterilizing 3 immunity against Lm, CD8+ T cells must recognize antigens bound to MHC-I proteins on the 4 surface of infected cells, an event that results in activation of the T cells and acquisition of 5 protective effector functions. Classical MHC-I proteins (MHC-Ia) have been studied for 6 decades, however, comparatively little is known about most of the non-classical MHC-I proteins 7 (MHC-Ib). We developed a MHC-Ia deficient mouse model of Lm infection to study the role of 8 MHC-Ib restricted T cells in the clearance of intracellular bacterial pathogens. Our central 9 hypothesis is that Lm-immune mice contain memory CD8+ T cells that recognize novel MHC-Ib 10 proteins, and that these T cells play a significant role in the clearance of secondary Lm infection. 11 In preliminary studies, we showed that CD8+ T cells that recognize antigen in the context of a 12 novel (not M3) MHC-Ib protein are activated during Lm infection. We have identified nine 13 murine MHC-Ib genes as likely candidates to express proteins that could serve as antigen 14 presenting molecules during infection. In this application, we propose to: 1) develop a panel of 15 human macrophage-like cells transfected with each of the nine candidate MHC-Ib genes and 2) 16 use the MHC-Ib transfectants to determine how many different MHC-Ib proteins are capable of 17 presenting antigen to T cells during Lm infection. These studies will help to define the role of 18 MHC-Ib restricted T cells in protective immune responses against Lm and may facilitate the 19 identification of new classes of antigens for all intracellular bacterial pathogens. Since most 20 MHC-Ib proteins are non-polymorphic, antigens that bind to MHC-Ib proteins are likely to be 21 recognized by most, if not all of the individuals in a given population. This makes MHC-Ib 22 antigens particularly attractive candidates for inclusion in vaccines designed to protect against 23 infection with intracellular bacterial pathogens. PUBLIC HEALTH RELEVANCE: One of the significant hurdles faced in trying to design vaccines to protect against infection with bacteria that can survive inside host cells is the identification of antigens that will be recognized by all individuals, regardless of their blood type (MHC haplotype). In this study, we will characterize a subset of T cells that recognize antigens derived from Listeria monocytogenes bound to MHC-Ib proteins, a class of proteins that is non- polymorphic (displays little variation among individuals) in both mice and humans. These studies have the potential to lead to new therapeutic strategies to protect against infections with a variety of intracellular bacteria, including prevalent human pathogens such as Mycobacteria tuberculosis and Chlamydia trachomatis.

描述（由申请人提供）： 1 单核细胞增生李斯特氏菌 (Lm) 是 B 类优先病原体，可引起 2 种食源性疾病的爆发，发病率和死亡率很高。为了实现针对 Lm 的灭菌 3 免疫，CD8+ T 细胞必须识别与受感染细胞 4 表面上的 MHC-I 蛋白结合的抗原，这一事件会导致 T 细胞激活并获得 5 种保护性效应功能。经典 MHC-I 蛋白 (MHC-Ia) 的研究已有 60 年之久，然而，人们对大多数非经典 MHC-I 蛋白 7 (MHC-Ib) 知之甚少。我们开发了 Lm 感染的 MHC-Ia 缺陷小鼠模型，以研究 8 MHC-Ib 限制性 T 细胞在清除细胞内细菌病原体中的作用。我们的核心 9 假设是，Lm 免疫小鼠含有识别新型 MHC-Ib 10 蛋白的记忆 CD8+ T 细胞，并且这些 T 细胞在清除继发性 Lm 感染中发挥着重要作用。 11 在初步研究中，我们发现在 12 种新型（非 M3）MHC-Ib 蛋白背景下识别抗原的 CD8+ T 细胞在 Lm 感染期间被激活。我们已经鉴定出 9 个 13 鼠 MHC-Ib 基因可能是表达蛋白质的候选基因，这些蛋白质可在感染期间充当抗原 14 呈递分子。在此应用中，我们建议：1) 开发一组 15 个人类巨噬细胞样细胞，转染 9 个候选 MHC-Ib 基因中的每一个，2) 16 使用 MHC-Ib 转染子来确定有多少种不同的 MHC-Ib 蛋白能够在 Lm 感染期间向 T 细胞呈递抗原。这些研究将有助于明确 18 MHC-Ib 限制性 T 细胞在针对 Lm 的保护性免疫反应中的作用，并可能有助于 19 所有细胞内细菌病原体新类别抗原的鉴定。由于大多数 20 种 MHC-Ib 蛋白是非多态性的，因此与 MHC-Ib 蛋白结合的抗原很可能被给定群体中的大多数（如果不是全部）个体识别。这使得 MHC-Ib 22 抗原成为特别有吸引力的候选者，可以包含在旨在预防 23 细胞内细菌病原体感染的疫苗中。公共卫生相关性：在尝试设计疫苗以防止宿主细胞内存活的细菌感染时，面临的重大障碍之一是识别所有个体都能识别的抗原，无论其血型（MHC 单倍型）如何。在这项研究中，我们将表征 T 细胞子集的特征，这些 T 细胞能够识别与 MHC-Ib 蛋白结合的单核细胞增多性李斯特菌衍生的抗原，MHC-Ib 蛋白是一类在小鼠和人类中都具有非多态性（个体间差异很小）的蛋白。这些研究有可能带来新的治疗策略，以防止多种细胞内细菌的感染，包括结核分枝杆菌和沙眼衣原体等常见的人类病原体。