Department of Biomedical Engineering , Vanderbilt University , Nashville , Tennessee 37235 , United States.
Department of Pathology, Microbiology, and Immunology , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States.
ACS Nano. 2019 Oct 22;13(10):10939-10960. doi: 10.1021/acsnano.9b00326. Epub 2019 Oct 4.
Tissue-resident memory T cells (T) patrol nonlymphoid organs and provide superior protection against pathogens that commonly infect mucosal and barrier tissues, such as the lungs, intestine, liver, and skin. Thus, there is a need for vaccine technologies that can induce a robust, protective T response in these tissues. Nanoparticle (NP) vaccines offer important advantages over conventional vaccines; however, there has been minimal investigation into the design of NP-based vaccines for eliciting T responses. Here, we describe a pH-responsive polymeric nanoparticle vaccine for generating antigen-specific CD8 T cells in the lungs. With a single intranasal dose, the NP vaccine elicited airway- and lung-resident CD8 T cells and protected against respiratory virus challenge in both sublethal (vaccinia) and lethal (influenza) infection models for up to 9 weeks after immunization. In elucidating the contribution of material properties to the resulting T response, we found that the pH-responsive activity of the carrier was important, as a structurally analogous non-pH-responsive control carrier elicited significantly fewer lung-resident CD8 T cells. We also demonstrated that dual-delivery of protein antigen and nucleic acid adjuvant on the same NP substantially enhanced the magnitude, functionality, and longevity of the antigen-specific CD8 T response in the lungs. Compared to administration of soluble antigen and adjuvant, the NP also mediated retention of vaccine cargo in pulmonary antigen-presenting cells (APCs), enhanced APC activation, and increased production of T-related cytokines. Overall, these data suggest a promising vaccine platform technology for rapid generation of protective CD8 T cells in the lungs.
组织驻留记忆 T 细胞(T 细胞)在非淋巴器官中巡逻,并为常见感染黏膜和屏障组织(如肺、肠、肝和皮肤)的病原体提供卓越的保护。因此,需要开发能够在这些组织中诱导强大、保护性 T 细胞反应的疫苗技术。纳米颗粒(NP)疫苗相对于传统疫苗具有重要优势;然而,对于设计基于 NP 的疫苗以引发 T 细胞反应的研究甚少。在这里,我们描述了一种用于在肺部产生抗原特异性 CD8 T 细胞的 pH 响应性聚合物纳米颗粒疫苗。单次鼻腔内给药,NP 疫苗可诱导气道和肺驻留 CD8 T 细胞,并在接种疫苗后长达 9 周内保护免受亚致死(牛痘)和致死(流感)感染模型中的呼吸道病毒挑战。在阐明材料特性对产生的 T 细胞反应的贡献时,我们发现载体的 pH 响应活性很重要,因为结构类似的非 pH 响应对照载体可诱导的肺驻留 CD8 T 细胞明显减少。我们还证明,在相同的 NP 上双重递送蛋白抗原和核酸佐剂可大大增强肺部抗原特异性 CD8 T 细胞反应的幅度、功能和持久性。与施用可溶性抗原和佐剂相比,NP 还介导疫苗货物在肺部抗原呈递细胞(APC)中的保留、增强 APC 激活和增加 T 相关细胞因子的产生。总体而言,这些数据表明这是一种有前途的肺部保护性 CD8 T 细胞快速生成的疫苗平台技术。
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