CD8 T cell and B cell collaboration following subunit vaccination

项目总结 一些迄今为止最成功的疫苗，包括针对致命病毒天花、麻疹、 腮腺炎和风疹由减毒的病毒颗粒组成，能够引起体液和细胞病变。 豁免权。然而，由于通过活体感染来保护许多病原体是不可行的，包括 艾滋病毒、疟疾、结核病和癌症，都需要替代疫苗方法。单次免疫 与蛋白质亚单位抗原和模式识别受体和CD40激动剂的组合 (联合佐剂亚单位疫苗)产生大量的CD8和CD4T细胞反应，即 比病毒载体在小鼠和非人类灵长类动物中通常诱导的病毒要大得多。vt.给出 这个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。 在过去的十年里，对免疫和感染的研究揭示了共同和不同的途径 用于产生免疫记忆。我们记录了一种独特的新陈代谢程序 通过扩增疫苗激发的T细胞，以及对细胞因子(IL-15、IL-27)和转录因子的要求 (Tbet，Eome)，对于感染引起的T细胞的扩张是必不可少的。这些差异使我们得出了 质疑之前被认为对产生CD8 T细胞反应不重要的其他因素，例如 因为抗原特异性B细胞的同时激活和增殖。考虑到不成比例的扩张 在亚单位免疫后很早的时候，B细胞似乎可以提供 对随后的CD8 T细胞反应的共刺激支持，直接或间接的。初步数据 支持这一不同寻常的主张。事实上，初步数据也显示CD8 T细胞反应 同样有益于亚单位疫苗的抗体反应。 我们还不知道整合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。我们的提案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1)B细胞抗原的作用 CD8 T细胞存活和细胞命运决定中的递呈和细胞因子的产生 B细胞在CD8T细胞记忆形成和维持中的作用，以及3)抗原-T细胞的作用机制。 特异性CD8T细胞影响B细胞的活化和抗体的形成。

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.