Memory CD8 T cell immunity to Plasmodium liver stage infec

描述（由申请人提供）：有明确证据表明，CD8 T细胞对啮齿动物疟原虫（P. berghei或P. yoelii）的环孢子子蛋白的反应可以在BALB/c小鼠的肝脏阶段阻止感染，从而预防疟疾的症状性血液阶段。在过去的十年中，我们的实验室花费了大量的精力来开发刺激和分析感染和接种后CD8 T细胞记忆反应的方法。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性CD8 T细胞介导的保护性免疫的免疫学机制。正如本提案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，可以产生伯氏假单胞菌环孢子虫(CS)-表位特异性记忆CD8 T细胞，这种细胞可以为BALB/c小鼠提供终身保护，抵御疟原虫孢子虫（spz）的多重攻击。我们使用该模型来确定，cs特异性记忆CD8 T细胞的灭菌免疫需要超过一个大的（占CD8 T细胞的20%），但需要确定的频率（占所有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性CD8 T细胞介导的针对疟原虫感染肝脏阶段的保护性免疫的基本免疫机制，这些信息可能对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实现这一长期目标：确定BALB/c小鼠抗伯氏疟原虫感染所需的cs特异性CD8 T细胞的大阈值是否可推广到其他疟原虫物种/表位或其他小鼠品系。目标2。确定cs特异性记忆CD8 T细胞如何保护肝脏期疟原虫感染。目标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CD8 T细胞对疟原虫攻击提供绝育免疫所需的阈值。目标4。确定不相关病原体的反复感染是否导致cs特异性记忆CD8 T细胞的消耗并损害无菌免疫。

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.