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进入促进长期病原体的调节器 特定的CD4+和CD8+ T细胞反应，并提供受保护的细胞介导的免疫功能。我们以前的研究 确定了使用CD40和TLR激动剂（CD40/TLR）的分子调整 在小鼠和素数中生活的T细胞群体，但是为什么这种方法如此有效。我们相信如果 我们可以理解为什么此调整与其他调节器或感染引起的反应不同，然后 将有助于疫苗的合理设计，以产生受保护的细胞介导的免疫力。我们已经记录了 疫苗吸收的T细胞（TVAX）与感染引起的T细胞（TINF）不同，这包括一个独特的 对于TVAX生成的细胞因子IL-27的代谢程序和意外要求。另外， 树突状细胞的专门子集（CDC1）产生IL-27的能力可以预测疫苗的幅度 引起CD8+ T细胞的扩展和记忆形成。我们最近的研究确定了IL-27依赖性 TVAX中的C-Myc转录签名与T细胞增殖和存活有关。我们 开发了一种计算模型，该模型在数学上概括了T细胞扩展数据 体内抗原挑战研究。这种无监督的分析表明，该分析能够迅速适应 在T细胞启动的主动性下，促进与APC的T细胞相互作用是幅度的主要预测指标 和T细胞响应的质量。基于这些数据集将使用T – DC相互作用的插入成像 以及对IL-27，DC函数和C-MYC途径的操纵以了解机械确定器 组合的CD40L/TLR调整。这些数据集将集​​成到基于随机代理的 数学模型，以预测和验证TVAX组中涉及的关键事件。提出的研究 将三个生产实验室及其各自专业知识的综合努力汇总在一起 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 建模以了解调整引诱的细胞免疫的分子基础。