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介导的免疫力，以病原体 仍然是该领域的主要挑战，并且与多种原生动物寄生虫有关。 然而，在实验环境中，使用复制缺陷型活微生物提供了一种方法， 产生有效的病原体特异性CD 4+和CD 8 + T细胞应答，但仍存在许多问题 让免疫系统识别和处理这些抗原的规则， 减毒微生物例如，即使是单次低剂量的非复制型疫苗CPS 刚地弓形虫菌株是一种强寄生虫特异性CD 4+和CD 8 + T细胞应答， 提供长久的记忆。这种反应依赖于BATF 3依赖性树突细胞 （BATF 3 DC）参与交叉呈递和IL-12产生，但我们的研究表明， 这些BATF 3 DC不直接与活的寄生虫相互作用，但直接感染的细胞是 需要T细胞启动。这些观察结果使我们假设，有一种途径， 其经历凋亡的感染细胞代表BATF 3的寄生虫抗原的来源 区议会因此，我们将使用各种独特的微生物工具（荧光报告，寄生虫 营养缺陷型、表达Cre的寄生虫）和小鼠品系（BATF 3 KO、独特报告基因和小鼠 其表达白喉毒素α亚单位的诱导形式）结合我们的成像 专业知识来解决我。如果处理和呈递CPS抗原需要BATF 3 DC 和二.干扰感染细胞的死亡是否可以用来修改CPS- 诱导反应。

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.