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: 10392126
• 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/10392126
• 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; 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; 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; 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.

羔羊实验室研究的重点是确定疟疾免疫发病发生的机制。避避剂实验室是在T细胞生物学中工作的主要实验室之一，能够精确测量多克隆T细胞群体的亲和力谱。我们将共同解决该提案的长期目标，即在疟原虫感染过程中定义T细胞反应的显着特征，从而驱动疟疾的病理。据估计，全世界每年有超过5亿人感染了疟疾，导致50万人死亡。 T细胞对引起疟疾的疟原虫的反应对于策划诸如吞噬作用和抗体产生的免疫效应机制至关重要，以控制寄生虫。然而，T细胞也负责感染的发病机理。确定疟疾中有益的致病性T细胞与致病性T细胞的特征尚不完全理解。在这里，我们建议CD8 T细胞对质子肽反应的亲和力塑造了膨胀细胞的曲目并深刻改变其功能，进而影响发病机理。尽管其他人已经鉴定出在疟原虫感染中免疫主导的T细胞表位，但随着感染的发展，我们对这些致病性T细胞的抗原反应性概况知之甚少。通常，据信高亲和力T细胞占主导任何多克隆T细胞反应，但我们的初步数据不支持这一点，这些数据清楚地表明，低亲和力T细胞占致病性抗质量响应的80％。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独特特征，它会导致器官特异性损伤，因为与高亲和力CD8 T细胞相比，具有低亲和力T细胞受体的CD8 T细胞会诱导交叉呈现的脑部微血管内皮细胞（BMECS）中的交叉表现不同的反应。拟议工作的理由是，T细胞反应对于与疟疾相关的器官特异性攻击至关重要，对T细胞反应的更全面的了解将为新型抗马利亚干预以及未来疫苗的合理使用和设计提供关键信息。 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如何识别寄生虫抗原的背景。