Mechanisms of combined CD40/TLR adjuvant-elicited cellular immunity

项目摘要 疫苗开发中的主要挑战之一是获得促进长寿病原体的佐剂。 特异性的CD4+和CD8+T细胞反应，并提供保护性细胞介导的免疫。我们之前的研究 发现了一种使用CD40和TLR激动剂(CD40/TLR)的分子佐剂，可诱导保护性长时间 小鼠和灵长类动物体内的活T细胞群，但为什么这种方法如此有效尚不清楚。我们相信，如果 我们可以理解为什么这种佐剂不同于其他佐剂或感染诱导的反应 将有助于合理设计疫苗，以产生保护性细胞介导的免疫。我们已经记录了 疫苗诱导的T细胞(Tvax)不同于感染诱导的T细胞(Tinf)，这包括一种独特的 代谢程序和细胞因子IL-27对TVAX生成的意外需求。此外， 树突状细胞的一个特殊亚群(CDc1)产生IL-27的能力可以预测疫苗的大小- 诱导CD8+T细胞扩增和记忆形成。我们最近的研究已经确定了一种依赖IL-27的 Tvax中与T细胞增殖和存活相关的c-Myc转录信号。我们 开发了一个计算模型，它从数学上概括了源自 体内抗原挑战研究。这一非监督分析表明，这种佐剂迅速 在T细胞启动时促进T细胞与APC的相互作用是大小的主要预测因素 以及T细胞反应的质量。基于这些数据集将使用T-DC相互作用的活体成像 以及对IL-27、DC功能和c-Myc通路的操纵以了解机制决定因素 CD40L/TLR联合佐剂。这些数据集将被集成到基于随机代理的 用于预测和验证TVAX形成过程中的关键事件的数学模型。建议进行的研究 汇聚三个生产性实验室的共同努力及其在佐剂方面的各自专业知识 发现、CD8+T细胞生物学、细胞因子和转录网络、多光子成像和计算 为了了解佐剂诱导的细胞免疫的分子基础而进行的建模。

Project Summary One of the major challenges in vaccine development is access to adjuvants that promote long-lived pathogen specific CD4+ and CD8+ T cell responses and provide protective cell mediated immunity. Our previous studies identified a molecular adjuvant that uses CD40 and TLR agonists (CD40/TLR) that induces protective long- lived T cell populations in mice and primates but why this approach is so effective is unclear. We believe that if we can understand why this adjuvant is different from other adjuvants or infection induced responses then it will help in the rational design of vaccines to generate protective cell mediated immunity. We have documented that vaccine-elicited T cells (Tvax) are distinct from infection-elicited T cells (Tinf) and this includes a unique metabolic program and unanticipated requirement for the cytokine IL-27 for Tvax generation. In addition, the ability of a specialized subset of dendritic cells (cDC1), to produce IL-27 predicts the magnitude of vaccine- elicited CD8+ T cell expansion and memory formation. Our recent studies have identified an IL-27-dependent c-Myc transcriptional signature within Tvax that is associated with T cell proliferation and survival. We developed a computational model which mathematically recapitulates T cell expansion data derived from antigen challenge studies in vivo. This unsupervised analysis indicates that the ability of this adjuvant to rapidly promote T cell interactions with APC at the initiation of T cell priming is the major predictor of the magnitude and quality of the T cell response. Based on these data sets will use intravital imaging of T–DC interactions and the manipulation of IL-27, DC functions and c-Myc pathways to understand the mechanistic determinants of the combined CD40L/TLR adjuvant. These data sets will be integrated into a stochastic agent-based mathematical model to predict and validate the key events involved in Tvax formation. The proposed studies bring together the combined efforts of three productive laboratories and their respective expertise in adjuvant discovery, CD8+ T cell biology, cytokine and transcriptional networks, multi photon imaging, and computational modeling in order to understand the molecular basis for adjuvant-elicited cellular immunity.