CD8 T cell and B cell collaboration following subunit vaccination

亚单位疫苗接种后 CD8 T 细胞和 B 细胞协作

基本信息

批准号：
10450847
负责人：
Ross M Kedl
金额：
$ 48.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450847
关键词：
Adjuvant Agonist Animal Model Antibodies Antibody Formation Antibody Response Antigen Presentation Antigen-Presenting Cells Antigens Attenuated Automobile Driving B-Cell Activation B-Lymphocytes Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD8B1 gene CXCR3 gene Cell Survival Cells Cellular Immunity Clinical Collaborations Cross Presentation Data Dendritic cell activation Development Dissection FDA approved Formulation Generations HIV Herpesvirus 1 Humor Humoral Immunities Immune response Immune system Immunity Immunization Immunologic Memory Immunologics Infection Infectious Agent Interleukin-15 Listeria monocytogenes Lymphocyte Biology Lymphocytic choriomeningitis virus Maintenance Malaria Malignant Neoplasms Measles Memory Metabolic Modeling Mumps Mus Natural Immunity Nature OX40 Pathway interactions Pattern recognition receptor Positioning Attribute Preventive vaccine Primates Process Production Protein Subunits Publishing Regulation Role Rubella Signal Transduction Subunit Vaccines T cell response T memory cell T-Lymphocyte TNFRSF5 gene TNFSF5 gene Testing Tuberculosis Vaccination Vaccine Adjuvant Vaccine Design Vaccine Production Vaccines Vaccinia virus Variola major virus Viral Viral Vector cell motility clinically relevant cytokine cytotoxic CD8 T cells defined contribution effector T cell experience mouse model nonhuman primate novel particle pathogen programs response success therapeutic vaccine transcription factor vaccination strategy vaccine candidate vaccine formulation vaccine platform vaccine response

项目摘要

PROJECT SUMMARY Some of the most successful vaccines to date, including those against the deadly viruses small pox, measles, mumps, and rubella, comprise attenuated viral particles, capable of inducing both humoral and cellular immunity. However, because protection through live infection is not feasible for many pathogens, including HIV, malaria, tuberculosis, and cancer, alternative vaccine approaches are needed. A single immunization with a protein subunit antigen and a combination of agonists toward pattern recognition receptors and CD40 (combined-adjuvant subunit vaccine) generates a magnitude of CD8+ and CD4+ T cell responses that is exponentially larger than those typically induced by viral vectors in both mice and non-human primates. Given the clinical promise of this vaccine platform, the careful study of the mechanisms controlling its potency may uncover novel targets for the development of more effective prophylactic and therapeutic vaccines. Over the past decade, studies of immunization and infection have revealed shared and distinct pathways utilized in the generation of immunological memory. We have documented a unique metabolic program used by expanding vaccine-elicited T cells, and requirements for cytokines (IL-15, IL-27) and transcription factors (Tbet, Eomes) that are dispensable for the expansion of infection-elicited T cells. These discrepancies led us to question other factors previously thought to be unimportant for the generation of CD8+ T cell responses, such as the concurrent activation and proliferation of antigen-specific B cells. Given the disproportionate expansion of B cells very early following subunit immunization, it seemed plausible that B cells could provide costimulatory support for the ensuing CD8+ T cell response, either directly, or indirectly. Preliminary data support this unconventional proposition. In fact, preliminary data also show that CD8+ T cell responses likewise benefit the antibody response to subunit vaccination. We do not yet understand the underlying mechanisms that integrate B cells and CD8+ T cells for the generation of long-lived cellular and humoral immunity. Our proposal will use classic immunological approaches to fully elucidate, specific to the context of subunit vaccination, 1) the role of B cell antigen presentation and cytokine production in the regulation of CD8+ T cell survival and cell fate determination, 2) the role of B cells in CD8+ T cell memory formation and maintenance, and 3) the mechanisms by which antigen- specific CD8+ T cells influence B cell activation and antibody formation.

项目概要迄今为止一些最成功的疫苗，包括针对致命病毒天花、麻疹、腮腺炎和风疹包含减毒病毒颗粒，能够诱导体液和细胞免疫。然而，由于通过活感染进行保护对于许多病原体来说是不可行的，包括艾滋病毒、疟疾、结核病和癌症需要替代疫苗方法。单次免疫具有蛋白质亚基抗原以及针对模式识别受体和 CD40 的激动剂组合（联合佐剂亚单位疫苗）产生一定程度的 CD8+ 和 CD4+ T 细胞反应，比小鼠和非人类灵长类动物中病毒载体通常诱导的结果呈指数级增长。给定该疫苗平台的临床前景，对其效力控制机制的仔细研究可能会发现开发更有效的预防性和治疗性疫苗的新目标。在过去的十年中，免疫和感染的研究揭示了共同和不同的途径用于免疫记忆的产生。我们记录了一个独特的代谢计划通过扩大疫苗诱导的 T 细胞，以及对细胞因子（IL-15、IL-27）和转录因子的需求（Tbet，Eomes）对于感染引起的 T 细胞的扩增是可有可无的。这些差异导致我们质疑以前认为对 CD8+ T 细胞反应的产生不重要的其他因素，例如抗原特异性 B 细胞同时激活和增殖。鉴于不成比例的扩张亚单位免疫后很早就出现了 B 细胞，看来 B 细胞可以提供直接或间接地对随后的 CD8+ T 细胞反应提供共刺激支持。初步数据支持这个非常规的主张。事实上，初步数据也显示CD8+ T细胞反应同样有利于亚单位疫苗接种的抗体反应。我们还不了解 B 细胞和 CD8+ T 细胞整合的潜在机制产生长寿命的细胞和体液免疫。我们的建议将使用经典的免疫学针对亚单位疫苗接种的具体情况，充分阐明的方法，1) B 细胞抗原的作用 CD8+ T 细胞存活和细胞命运决定调节中的表达和细胞因子产生，2) B 细胞在 CD8+ T 细胞记忆形成和维持中的作用，以及 3) 抗原- 特定的 CD8+ T 细胞影响 B 细胞激活和抗体形成。