Memory CD8 T cell immunity to Plasmodium liver stage infec

描述(由申请人提供)：有明确的证据表明，CD8 T细胞对啮齿动物疟原虫(伯氏疟原虫或约氏疟原虫)的环子孢子蛋白的反应可以阻止BALB/c小鼠在肝脏阶段的感染，从而防止疟疾的症状血液期。在过去的十年里，我们的实验室花费了大量的精力来开发方法来刺激和分析感染和疫苗接种后的CD8 T细胞记忆反应。我们进入疟疾领域的最初目标不是开发疫苗，而是设计一个模型系统，使我们能够研究由记忆CD8 T细胞介导的保护性免疫的免疫学机制。正如这项建议的初步数据和最近发表在PNAS1上的一篇文章所示，我们的实验室已经开发出一种免疫策略，以产生伯氏疟原虫环子孢子(CS)-表位特异性记忆CD8 T细胞，基本上为BALB/c小鼠提供终身保护，使其免受疟原虫子孢子(SPZ)的多重攻击。我们使用这个模型来确定CS特异性记忆CD8T细胞超过一个大的(CD8T细胞的20%)，但杀菌免疫所需的可定义频率(&gt；所有PBL的1%)。我们的长期目标是利用这个定量模型系统来了解导致记忆CD8 T细胞介导的保护性免疫的基本免疫学机制，这些信息可能对于合理设计有效的疟疾疫苗至关重要。我们将通过以下具体目标来解决这一长期目标：目的1.确定保护BALB/c小鼠免受伯氏疟原虫感染所需的CS特异性CD8 T细胞的大阈值是否适用于其他疟原虫物种/表位或其他小鼠品系。目的2.确定CS特异性记忆CD8 T细胞对肝期疟原虫感染的保护作用。目的3.确定其他免疫效应细胞和途径的募集是否以及如何降低CS特异性CD8T细胞对疟原虫攻击提供灭菌免疫所需的阈值。目的4.确定反复感染无关病原体是否会导致CS特异性记忆CD8 T细胞的磨损并影响不育性免疫。 与公共卫生相关：疟疾亚单位疫苗领域的重点是改进抗原传递的媒介系统，这些经验方法可能会改进现有的传递平台，并可能揭示新的平台。然而，尽管对疟疾疫苗进行了40多年的研究，但我们仍然对疟疾感染的灭菌免疫所需的特定免疫机制知之甚少。解决这一知识差距将有助于合理设计疟疾疫苗，这也是本提案的目标。

DESCRIPTION (provided by applicant): Clear evidence exists that CD8 T cell responses to the circumsporozoite protein of the rodent Plasmodia (P. berghei or P. yoelii) can stop the infection at the liver stage in BALB/c mice, thus preventing the symptomatic blood stage of malaria. Our laboratory has spent considerable effort over the last decade developing approaches to stimulate and analyze CD8 T cell memory responses after infection and vaccination. Our initial goal in entering the malaria field was not to develop a vaccine, but instead to devise a model system that would permit us to study the immunological mechanisms resulting in protective immunity mediated by memory CD8 T cells. As shown in the preliminary data of this proposal and a recent publication in PNAS1, our laboratory has developed an immunization strategy to generate P. berghei circumsporozoite (CS)-epitope- specific memory CD8 T cells that provides essentially life-long protection of BALB/c mice against multiple challenges with Plasmodium sporozoites (spz). We used this model to determine that CS-specific memory CD8 T cells exceeding a large (>20% of CD8 T cells), but definable frequency (>1% of all PBL) were required for sterilizing immunity. Our long-term goal is to exploit this quantitative model system to understand the basic immunological mechanisms that result in memory CD8 T cell-mediated protective immunity against the liver stage of Plasmodium infection, information that could be critical for the rational design of efficacious vaccines against malaria. We will address this long-term goal through the following specific aims: Aim 1. Determine if the large threshold of CS-specific CD8 T cells required for protection of BALB/c mice against P. berghei infection is generalizable to other Plasmodium species/epitopes or other mouse strains. Aim 2. Determine how CS-specific memory CD8 T cells protect against liver stage Plasmodium infection. Aim 3. Determine if and how recruitment of other immune effector cells and pathways reduces the threshold required for CS-specific CD8 T cells to provide sterilizing immunity to Plasmodium challenge. Aim 4. Determine if recurring infections with unrelated pathogens result in attrition of CS-specific memory CD8 T cells and compromise sterilizing immunity. PUBLIC HEALTH RELEVANCE: Much emphasis in the field of subunit vaccines for malaria has been placed on improving the vector systems for antigen-delivery and these empirical approaches are likely to improve the existing delivery platforms and potentially reveal new platforms. However, despite the more than 40 years of research in malaria vaccines, we still know very little about the specific immune mechanisms required for sterilizing immunity to Plasmodium infection. Addressing this knowledge gap would aid in the rational design of malaria vaccines and is the goal of this proposal.