Pathogenic low affinity CD8 T cells in malaria

疟疾中的致病性低亲和力 CD8 T 细胞

• 批准号: 10490915
• 负责人: Brian D Evavold
• 金额: $ 65.36万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490915
• 关键词: Acute Lung Injury; Address; Adhesions; Affect; Affinity; Antibody Formation; Antigens; Antimalarials; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; CD8-Positive T-Lymphocytes; Cell Death; Cells; Cellular biology; Central Nervous System Viral Diseases; Cerebral Malaria; Cessation of life; Coupled; Data; Development; Disease; Disease Outcome; Event; Experimental Models; Frequencies; Future; GTP-Binding Protein alpha Subunits, Gs; Goals; Immune; Immune response; Immunodominant Epitopes; Impaired cognition; Individual; Infection; Infection Control; Interferon Type II; Interleukin-10; Intervention; Knowledge; Laboratories; Lead; Life Cycle Stages; Link; Liver; Liver Fibrosis; Malaria; Measures; Mediating; Mission; Modeling; Molecular; Nervous System Trauma; Neuraxis; Organ; Outcome; Parasitemia; Parasites; Pathogenesis; Pathogenicity; Pathology; Peptides; Persons; Phagocytosis; Plasmodium; Plasmodium berghei; Population; Public Health; Reaction; Research; Shapes; Stains; Survivors; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic Intervention; United States National Institutes of Health; Vaccine Design; Vaccines; Work; adaptive immunity; antigen-specific T cells; base; brain endothelial cell; cytokine; design; disability; human disease; immunopathology; insight; novel; novel marker; response; skills; therapy design; trafficking; two-dimensional

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.

兰姆实验室的研究重点是确定疟疾免疫发病机制。 Evavold 实验室是 T 细胞生物学领域领先的实验室之一，能够精确测量多克隆 T 细胞群的亲和力特征。我们将共同解决该提案的长期目标，即确定疟原虫感染期间 T 细胞反应的显着特征，从而驱动疟疾的病理学。据估计，全世界每年有超过 5 亿人感染疟疾，导致 50 万人死亡。 T 细胞针对引起疟疾的疟原虫寄生虫的反应对于协调免疫效应机制（例如吞噬作用和控制寄生虫血症的抗体产生）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 细胞与疟原虫肽反应的亲和力塑造了扩增细胞的所有功能，并深刻地改变了它们的功能，进而影响了发病机制。尽管其他人已经鉴定出在疟原虫感染中具有免疫显性的 T 细胞表位，但随着感染的进展，我们对这些致病性 T 细胞的抗原反应特性知之甚少。一般来说，人们认为高亲和力 T 细胞在任何多克隆 T 细胞反应中占主导地位，但我们的初步数据并不支持这一点，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% 以上。根据我们的初步数据，我们假设低亲和力 CD8 T 细胞的这种优势是疟原虫感染的一个独特特征，它会导致器官特异性损伤，因为具有低亲和力 T 细胞受体的 CD8 T 细胞在交叉呈递的脑微血管内皮细胞中诱导不同的反应。细胞（BMEC）与高亲和力 CD8 T 细胞相比。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型抗疟疾干预措施提供关键信息，例如以及未来的疫苗。我们计划测试我们的中心假设，从而通过追求以下三个具体目标来实现本申请的目标： 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：定义之间的功能差异疟原虫感染中低亲和力和高亲和力 CD8 T 细胞转运至中枢神经系统 目标 3：根据寄生虫抗原的识别方式，检验低亲和力 CD8 T 细胞在反应中占主导地位的假设。