Mechanisms of combined CD40/TLR adjuvant-elicited cellular immunity

CD40/TLR 联合佐剂引发细胞免疫的机制

• 批准号: 10578741
• 负责人: Thomas A Adams
• 金额: $ 61.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-25 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578741
• 关键词: Address; Adjuvant; Agonist; Antigen Presentation; Biological Models; Biomass; CD8-Positive T-Lymphocytes; Cell Communication; Cell Survival; Cellular Immunity; Cellular biology; Clonal Expansion; Computer Models; Cytokine Activation; Data; Data Set; Dendritic Cells; Development; Elements; Evaluation; Event; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic Transcription; Hexosamines; Histocompatibility Antigens Class I; Human Resources; Immune; Immunity; Immunologic Memory; Immunology; Infection; Interleukin-15; Laboratories; Mathematics; Mediating; Memory; Metabolic; Methods; Mitochondria; Modeling; Molecular; Mus; Natural Immunity; Pathway interactions; Population; Primates; Production; Productivity; Publishing; Reporter; Research; Role; Signal Pathway; Signal Transduction; Subunit Vaccines; System; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TCR Activation; TNFRSF5 gene; TNFSF5 gene; Testing; Vaccination; Vaccine Design; Vaccines; Validation; antigen challenge; c-myc Genes; cytokine; design; efficacy evaluation; fatty acid oxidation; gain of function; genetic approach; imaging approach; in vivo; innovation; intravital imaging; loss of function; mathematical model; multiphoton imaging; nonhuman primate; pathogen; predictive modeling; programs; rational design; response; transcription factor; vaccine development; vaccine trial

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.

项目摘要 疫苗开发的主要挑战之一是获得促进长寿命病原体的佐剂 特异性CD 4+和CD 8 + T细胞应答并提供保护性细胞介导的免疫。我们以前的研究 鉴定了一种分子佐剂，其使用CD 40和TLR激动剂（CD 40/TLR）诱导保护性长- 在小鼠和灵长类动物中存活的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， 将有助于疫苗的合理设计，以产生保护性细胞介导的免疫力。我们记录 疫苗诱导的T细胞（Tvax）与感染诱导的T细胞（Tinf）不同，这包括一个独特的 代谢程序和Tvax生成对细胞因子IL-27的非预期需求。此外该 树突状细胞（cDC 1）的一个专门子集产生IL-27的能力预测了疫苗的重要性。 引起CD 8 + T细胞扩增和记忆形成。我们最近的研究已经确定了IL-27依赖性 Tvax内与T细胞增殖和存活相关的c-Myc转录特征。我们 开发了一个计算模型，该模型在数学上概括了T细胞扩增数据， 体内抗原攻击研究。这种无监督的分析表明，这种佐剂快速免疫的能力， 在T细胞启动时促进T细胞与APC的相互作用是T细胞活化的主要预测因子。 和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，以了解其机制决定因素 CD 40 L/TLR佐剂的组合。这些数据集将被集成到一个随机的基于代理的 数学模型来预测和验证Tvax形成中涉及的关键事件。拟议的研究 汇集了三个生产实验室的共同努力及其各自在佐剂方面的专业知识， 发现，CD 8 + T细胞生物学，细胞因子和转录网络，多光子成像和计算 建模，以了解促排剂引起的细胞免疫的分子基础。