CD8 T cell and B cell collaboration following subunit vaccination

项目摘要 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， 免疫力然而，由于通过活感染的保护对于许多病原体是不可行的，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 用蛋白质亚单位抗原和针对模式识别受体和CD40的激动剂的组合 （联合佐剂亚单位疫苗）产生的CD8+和CD4 + T细胞反应的幅度， 在小鼠和非人灵长类动物中，比通常由病毒载体诱导的那些指数更大。给定 这种疫苗平台的临床前景，控制其效力的机制的仔细研究， 为开发更有效的预防和治疗疫苗发现新的靶点。 在过去的十年里，免疫和感染的研究揭示了共同的和不同的途径 用于产生免疫记忆。我们记录了一种独特的代谢程序， 通过扩增疫苗诱导的T细胞，以及对细胞因子（IL-15、IL-27）和转录因子的需求， (Tbet，Eomes），其用于扩增感染引起的T细胞。这些差异导致我们 质疑以前认为对CD8 + T细胞应答产生不重要的其他因素，例如 如抗原特异性B细胞的同时活化和增殖。考虑到不成比例的扩张 亚单位免疫后B细胞非常早期，B细胞可以提供 在一些实施方案中，所述共刺激因子直接或间接地支持随后的CD8 + T细胞应答。初步数据 支持这一非传统的主张。事实上，初步数据还显示，CD8 + T细胞应答 同样有益于亚单位疫苗接种的抗体应答。 我们还不了解整合B细胞和CD8 + T细胞的潜在机制， 产生长寿的细胞和体液免疫。我们的建议将使用经典的免疫学方法 具体到亚单位疫苗接种的情况，充分阐明1）B细胞抗原的作用 在调节CD8 + T细胞存活和细胞命运决定中的细胞因子呈递和细胞因子产生， B细胞在CD8 + T细胞记忆形成和维持中的作用，以及3）抗原-T细胞结合的机制。 特异性CD8 + T细胞影响B细胞活化和抗体形成。

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.