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

• 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
• 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

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.

项目摘要 迄今为止，一些最成功的疫苗，包括针对致命病毒的小痘，麻疹， 腮腺炎和红宝石包括减毒病毒颗粒，能够诱导体液和细胞 免疫。但是，由于通过现场感染保护对于许多病原体来说是不可行的，包括 需要HIV，疟疾，结核病和癌症，需要替代疫苗方法。一次免疫 与蛋白质亚基抗原以及对模式识别受体和CD40的激动剂的组合 （联合亚辅助亚基疫苗）产生大小的CD8+和CD4+ T细胞反应 指数大于通常由病毒向量引起的小鼠和非人类灵长类动物引起的。给出 这个疫苗平台的临床承诺，对控制其效力的机制的仔细研究可能 揭示了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，对免疫和感染的研究揭示了共同且不同的途径 用于免疫记忆的产生。我们已经记录了一个独特的代谢程序 通过扩展疫苗吸收的T细胞以及细胞因子的需求（IL-15，IL-27）和转录因子 （TBET，EOMES），可用于扩展感染引起的T细胞。这些差异导致我们 问题以前认为对CD8+ T细胞反应的产生不重要的其他因素， 作为抗原特异性B细胞的并发激活和增殖。考虑到不成比例的扩展 亚基免疫后，B细胞很早，B细胞可以提供B细胞似乎是合理的 对随后的CD8+ T细胞反应的共刺激支持，无论是直接或间接的。初步数据 支持这个非常规的主张。实际上，初步数据还表明CD8+ T细胞响应 同样，有益于亚基疫苗接种的抗体反应。 我们尚不了解整合B细胞和CD8+ T细胞的基本机制 长期寿命的细胞和体液免疫产生。我们的建议将使用经典的免疫学 完全阐明的方法，特定于亚基疫苗接种的情况，1）B细胞抗原的作用 CD8+ T细胞存活和细胞命运确定的调节中的表现和细胞因子产生，2） B细胞在CD8+ T细胞记忆形成和维持中的作用，以及3）抗原的机制 特定的CD8+ T细胞会影响B细胞激活和抗体形成。