Utilizing BATF3-dependent DC to generate vaccine-induced cell mediated immunity

项目摘要 疫苗的实施可以特异性地提高细胞对病原体的免疫力 仍然是该领域的一大挑战，与多种原生动物寄生虫有关。 然而，在实验环境中，使用复制缺陷的活微生物提供了一种方法 产生强大的病原体特异性的CD4+和CD8+T细胞反应，但仍有许多问题 关于允许免疫系统识别和处理这些抗原的规则 弱化的生物体。例如，即使是单次低剂量的非复制疫苗CPS 弓形虫株可诱导强烈的寄生虫特异性CD4+和CD8+T细胞反应 提供持久的内存。这种反应依赖于依赖于BATF3的树突状细胞 (BATF3 DC)参与交叉呈现和IL-12的产生，但我们的研究表明 这些BATF3树突状细胞不直接与活体寄生虫相互作用，但直接感染的细胞 是T细胞启动所必需的。这些观察结果让我们假设，在地球上 BATF3的寄生虫抗原来源是哪些感染细胞发生了凋亡？ 集散控制系统。因此，我们将使用各种独特的微生物工具(荧光记者、寄生虫 营养缺乏症、Cre-exressing寄生虫)和小鼠品系(BATF3 KO、Unique Report和小鼠 表达白喉毒素α亚单位的诱导形式)与我们的成像相结合 如果处理和呈递CPS抗原需要BATF3 DC 以及ii.是否可以使用干扰感染细胞死亡的方法来修改CPS- 诱发反应。

Project Summary The implementation of vaccines that can specifically boost cell mediated immunity to a pathogen has remained a major challenge in the field and is relevant to multiple protozoan parasites. However, in experimental settings the use of replication deficient live microbes provide one way to generate potent pathogen specific CD4+ and CD8+ T cells responses but many questions remain about the rules that allow the immune system to recognize and process the antigens from these attenuated organisms. For example, even a single low dose of the non-replicating vaccine CPS strain of Toxoplasma gondii elicits a robust parasite specific CD4+ and CD8+ T cell response that provides long-lived memory. This response is dependent on the BATF3-dependent dendritic cells (BATF3 DCs) involved in cross presentation and IL-12 production but our studies indicate that these BATF3 DCs do not directly interact with live parasites, but that directly infected cells are required for T cell priming. These observations lead us to hypothesize that there is a pathway in which infected cells undergoing apoptosis represent the source of parasite antigen for the BATF3 DCs. Therefore, we will use a variety of unique microbial tools (fluorescent reporters, parasite auxotrophs, Cre-exressing parasites) and mouse strains (BATF3 KO, unique reporters, and mice which express inducible forms of the diptheria toxin alpha subunit) combined with our imaging expertise to address I. If BATF3 DC are required for processing and presentation of CPS antigens and II. Whether interfering with the death of the infected cells can be used to modify the CPS- induced responses.