Molecular and cellular basis of Combined Adjuvant-Elicited Cellular Immunity

项目摘要 在Toll样受体和Toll样受体的激动剂存在下用抗原免疫 (TLR)和CD 40（TLR/CD 40联合免疫）可刺激免疫细胞的大量扩增。 抗原特异性CD 8 + T细胞，其指数大于由以下引起的应答： 单独的激动剂。不仅对这种疫苗接种的初级免疫应答是强有力的， 它还形成了长寿的CD 8 + T细胞记忆，可以防止未来的感染， 即使在不存在CD 4 + T细胞的情况下也能激发。这一点最近在非- 在人类灵长类动物中，疫苗产生的反应比 对典型病毒载体的反应。考虑到它的效力和临床潜力 疫苗佐剂平台，我们了解其分子和细胞是至关重要的 机械基础。我们最近有了一个惊人的发现， 对这一点的反应，以及相关的疫苗接种， 依赖于两种细胞因子（IL-27和IL-15）和两种转录因子（Tbet和 Eomes）。这是出乎意料的，因为这些因素中的任何一个的损失， 消除了对疫苗的反应，但对活疫苗的反应几乎没有影响。 病毒或细菌。因此，强大的亚单位疫苗引发的免疫背后的规则出现 与引导感染反应的基因有很大不同。这项建议会 使用尖端的方法和途径，以充分了解这一性质， i）IL-27和IL-15如何影响下游转录， 细胞因子，ii）Tbet和Eomes表达如何随后编程T细胞 活化和扩增，以及iii）这些因子如何介导T-DC和T-T相互作用 在联合佐剂疫苗接种后T细胞活化的最早事件期间。

Project Summary Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. Not only is the primary immune response to this vaccination robust, it also forms long lived, CD8+ T cell memory that can protect against future infectious challenge even in the absence of CD4+ T cells. This has been recently verified in non- human primates, where the vaccine produced responses exponentially stronger than responses to typical viral vectors. Given the potency and clinical potential for this vaccine adjuvant platform, it is critical that we understand its molecular and cellular mechanistic underpinnings. We recently made the surprising discovery that T cell responses to this, and related, vaccinations were unexpectedly and completely dependent on two cytokines (IL-27 and IL-15) and two transcription factors (Tbet and Eomes). This was unexpected because the loss of any one of these factors essentially ablates the response to the vaccine but has little to no effect on the response to live virus or bacteria. Thus, the rules behind robust subunit vaccine-elicited immunity appear to be substantially different than those guiding infectious responses. This proposal will use cutting edge methods and approaches to fully understand the nature of this difference and will test i) how IL-27 and IL-15 influence downstream transcriptional and cellular factors, ii) how Tbet and Eomes expression subsequently program T cell activation and expansion, and iii) how these factors mediate T-DC and T-T interactions during the earliest events of T cell activation after combined adjuvant vaccination.