Pathogenic low affinity CD8 T cells in malaria

Lamb实验室的研究重点是确定疟疾的免疫发病机制。Evavold实验室是T细胞生物学领域的领先实验室之一，具有精确测量多克隆T细胞群体亲和力的能力。我们将共同解决该提案的长期目标，即确定驱动疟疾病理的疟原虫感染期间T细胞反应的显著特征。据估计，全世界每年有5亿多人感染疟疾，造成50万人死亡。T细胞对引起疟疾的疟原虫的反应对于协调免疫效应机制（如吞噬和抗体产生）以控制寄生虫病至关重要。然而，T细胞也负责感染的发病机制。决定疟疾中有益T细胞与致病T细胞的特征尚不完全清楚。在这里，我们提出CD8 T细胞对疟原虫肽反应的亲和力塑造了扩增细胞的库，并深刻地改变了它们的功能，进而影响了发病机制。虽然其他人已经确定了在疟原虫感染中具有免疫优势的T细胞表位，但随着感染的进展，我们对这些致病性T细胞的抗原反应性谱知之甚少。一般认为，高亲和力T细胞主导任何多克隆T细胞反应，但我们的初步数据不支持这一观点，该数据清楚地表明，低亲和力T细胞占致病性抗疟原虫反应的80%。根据我们的初步数据，我们假设这种低亲和力CD8 T细胞的优势是疟原虫感染导致器官特异性损伤的独特特征，因为与高亲和力CD8 T细胞相比，低亲和力T细胞受体的CD8 T细胞在交叉呈递的脑微血管内皮细胞（BMECs）中诱导不同的反应。这项拟议工作的基本原理是，T细胞反应是与疟疾相关的器官特异性攻击的核心，对T细胞反应的更全面了解将为合理使用和设计新的抗疟疾干预措施以及未来的疫苗提供关键信息。我们计划通过以下三个具体目标来验证我们的中心假设，从而实现本应用的目标：目标1：证明低亲和力CD8 T细胞在实验性脑疟疾中具有致病性；目标2：定义在疟原虫感染中向中枢神经系统运输的低亲和力和高亲和力CD8 T细胞之间的功能差异；基于如何识别寄生虫抗原的背景，验证低亲和力CD8 T细胞主导应答的假设。

The focus of the research in the Lamb lab is to determine mechanisms of the immunopathogenesis of malaria. The Evavold lab is one of the leading laboratories working in T cell biology with the capability to precisely measure the affinity profile of polyclonal T cell populations. Together we will address the long-term goal of this proposal which is to define the salient features of the T cell response during Plasmodium infections that drives the pathology of malaria. It is estimated that annually more than 500 million people are infected with malaria worldwide resulting in 0.5 million deaths. T cell responses against the Plasmodium parasites that cause malaria are critical in orchestrating immune effector mechanisms such as phagocytosis and antibody production to control parasitemia. However, T cells are also responsible for the pathogenesis of infection. The features that determine beneficial versus pathogenic T cells in malaria are incompletely understood. Here we propose that the affinity of CD8 T cells reacting to Plasmodium peptides shapes the repertoire of expanded cells and profoundly alters their function, in turn impacting pathogenesis. Although others have identified T cell epitopes that are immunodominant in Plasmodium infections, we know very little about the antigen reactivity profile of these pathogenic T cells as infection progresses. In general, it is believed that high affinity T cells predominate any polyclonal T cell response, yet this is not supported by our preliminary data which clearly shows that low affinity T cells make up >80% of the pathogenic anti-Plasmodium response. Based on our preliminary data, we hypothesize that this predominance of low affinity CD8 T cells is a unique feature of Plasmodium infection that leads to organ specific damage because CD8 T cells with low affinity T cell receptors induce different responses in cross-presenting brain microvascular endothelial cells (BMECs) compared with high affinity CD8 T cells. The rationale for the proposed work is that T cell responses are central to the organ-specific attack associated with malaria, and a more comprehensive understanding of the T cell response will provide key information for the rational use and design of novel anti-malaria interventions as well as future vaccines. We plan to test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following three specific aims: Aim 1: Demonstrate that low affinity CD8 T cells are pathogenic in experimental cerebral malaria Aim 2: Define the functional differences between low and high affinity CD8 T cells trafficking to the CNS in Plasmodium infection Aim 3: Test the hypothesis that low affinity CD8 T cells predominate the response based on the context of how the parasite antigens are recognized.