CD4-Dependent help for mucosal vaccine responses

带有真菌病原体的肺部感染是艾滋病毒感染的一种常见的、往往是致命的并发症。新出现的数据表明，肺孢子虫还可能使未感染艾滋病毒的宿主的肺部疾病复杂化。该项目的长期目标是开发一种针对肺孢子虫的疫苗。为此，我们已经确定了一种新的肺孢子虫候选疫苗，称为迷你可信。我们将确定CD4+T淋巴细胞参与对可信疫苗的全身和粘膜免疫反应的机制。该项目将验证实验假设，即使用基本/增强疫苗策略，CD4+T淋巴细胞的帮助对于优化粘膜CD8+T细胞和对迷你可信的抗体反应是必要的。这些研究的目标将是确定在正常宿主中CD4+T淋巴细胞在疫苗反应中的作用。它们是为了补充为项目2提出的实验，这些实验将侧重于CD4非依赖疫苗的反应。除了迷你可信，我们还将在我们的模型系统中研究通过抗原发现核心确定的候选抗原。具体目标有4个： 1.验证在小型可信疫苗接种的初始阶段，在肺组织中获得最佳的CD8+和抗体反应所必需的CD4+T淋巴细胞的帮助这一概念。 2.验证T淋巴细胞CD40配体相互作用是肺组织最佳CD8+和抗体疫苗应答所必需的概念。 3.验证肺组织中CD8+和抗体疫苗的最佳应答需要STAT3和IL-17分泌的T淋巴细胞的概念。 4.验证CD40+和IL-17分泌的T淋巴细胞在非人灵长类局部疫苗应答中的作用。

Pulmonary infection with the fungal pathogen, Pneumocystis jirovecii, is a common and often fatal complication of HIV infection. Emerging data suggest that Pneumocystis may also complicate lung diseases in non-HIV-infected hosts. The long-term goal of this Program Project is to develop a vaccine against Pneumocystis. To that end, we have identified a novel vaccine candidate for Pneumocysfis termed mini-kexin. We will identify mechanisms through which CD4+ T-lymphocytes participate in systemic and mucosal immune responses to the kexin vaccine. This project will test the experimental hypothesis that CD4+ T-lymphocyte help is necessary for optimal mucosal CD8+ T-cell and antibody responses to mini-kexin using a prime/boost vaccine strategy. The goal of these studies will be to define the role of CD4+ T-lymphocytes in vaccine responses in normal hosts. They are meant to complement experiments proposed for Project 2 that will focus on CD4-independent vaccine responses. In addition to mini-kexin, we will also investigate in our model systems antigen candidates identified through the Antigen Discovery Core. There are 4 Specific Aims: 1. To test the concept that CD4+ T-lymphocyte help is necessary during the priming phase of mini-kexin vaccination for optimal CD8+ and antibody responses in lung tissue. 2. To test the concept that T-lymphocyte CD40 ligand interactions are necessary for optimal CD8+ and antibody vaccine responses in lung tissue. 3. To test the concept that Stat3 and IL-17-secrefing T-lymphocytes are required for optimal CD8+ and antibody vaccine responses in lung tissue. 4. To validate the role of CD40+ and IL-17-secrefing T-lymphocytes in local vaccine responses of nonhuman primates.