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.