Memory CD8 T cell immunity to Plasmodium liver stage infec

描述（由申请方提供）：有明确证据表明，CD 8 T细胞对啮齿类疟原虫（伯氏疟原虫或约氏疟原虫）环子孢子蛋白的应答可以在BALB/c小鼠的肝脏阶段停止感染，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相当大的努力来开发方法来刺激和分析感染和疫苗接种后的CD 8 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CD 8 T细胞介导的保护性免疫的免疫机制。如该提议的初步数据和PNAS 1中最近的出版物所示，我们的实验室已经开发了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CD 8 T细胞，其为BALB/c小鼠提供基本上终身的保护以对抗疟原虫子孢子（spz）的多次攻击。我们使用该模型来确定CS特异性记忆CD 8 T细胞超过大量（>20%的CD 8 T细胞），但可确定的频率（>1%的所有PBL）是消除免疫所需的。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CD 8 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实现这一长期目标：目标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CD 8 T细胞的大阈值是否可推广到其他疟原虫种属/表位或其他小鼠品系。目标二。确定CS特异性记忆CD 8 T细胞如何保护肝脏免受疟原虫感染。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CD 8 T细胞对疟原虫攻击提供杀菌免疫所需的阈值。目标4。确定不相关病原体的反复感染是否会导致CS特异性记忆CD 8 T细胞的磨损并损害灭菌免疫。 公共卫生相关性：疟疾亚单位疫苗领域的重点一直放在改进抗原递送的载体系统上，这些经验方法可能会改进现有的递送平台并可能揭示新的平台。然而，尽管疟疾疫苗的研究已经超过40年，我们仍然对消除对疟原虫感染的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疟疾疫苗的合理设计，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.