Regulation of Plasmodium-specific CD4+ T Cells

疟原虫特异性 CD4 T 细胞的调节

• 批准号: 9214981
• 负责人: Noah Sullivan Butler
• 金额: $ 11.13万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-26 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214981
• 关键词: Address; Adoptive Transfer; Affect; Agonist; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacterial Infections; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cell surface; Cells; Cellular Immunity; Cellular biology; Characteristics; Child; Chronic; Communicable Diseases; Communication; Comparative Study; Contracts; Cytokine Signaling; Data; Disease; Dissection; Emergency Situation; Employee Strikes; Environment; Exhibits; Experimental Models; Generations; Genetic; Goals; Helper-Inducer T-Lymphocyte; Host resistance; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunology; Immunotherapy; Infection; Inflammation; Inflammatory; Intervention; Link; Malaria; Malignant Neoplasms; Mediating; Modeling; Mus; Parasite Control; Parasites; Pathway interactions; Physiological; Plasmodium; Plasmodium falciparum; Proteins; Publishing; Reagent; Regulation; Reporting; Research; Resistance; Risk; Role; Severities; Staging; Stimulus; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Virulence; Virus Diseases; Work; base; burden of illness; functional restoration; global health; hemozoin; immunoregulation; improved; improved functioning; insight; killings; member; microbial; pathogen; receptor; receptor expression; research study; therapeutic target; tumor necrosis factor ligand superfamily member 4; tumor necrosis factor receptor superfamily member 4

PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Malaria affected more than 200 million people last year, killing nearly 600,000. Antibody responses that target the parasite are essential for controlling parasite replication and limiting the severity of malaria. Potent antibody responses and optimally stimulated B cells require `help' from CD4+ T cells. Our published work has shown that CD4+ T cell function is markedly impaired following Plasmodium infection. We linked the reduced function of CD4+ T cells to the induction of co-inhibitory receptor expression, a class of T cell surface expressed proteins that directly limit the ability of CD4+ T cells to orchestrate protective immune responses against microbial pathogens. We further showed that blocking the activity of co-inhibitory receptors during malaria restored CD4+ T cell function, promoted strong antibody responses and accelerated parasite control and clearance from the infected host. Recently, we identified that we can also restore the function of Plasmodium-specific CD4+ T cells by activating OX40, a member of a class of T cell stimulating receptors. Our new data show that therapeutically stimulating the OX40 receptor during the second week of experimental Plasmodium infection overcomes co- inhibitory networks, markedly improves CD4+ T cell activity and secreted antibody responses, and limits malaria parasite replication. Importantly, we also identified parallels in children infected with P. falciparum, establishing the relevance and significance of our discoveries and strengthening the scientific premise of the current proposal. In this project we apply new cellular, genetic and parasitological reagents to study how the OX40 receptor regulates communication between parasite specific CD4+ T cells and B cells and the generation of antibody responses. Our scientific questions and experimental approaches facilitate our long- term goal to identify new immune-based approaches to therapeutically stimulate host resistance against malaria. Our goal is addressed by three specific aims that will determine: 1) the distinct characteristics of Plasmodium infection that uniquely regulate the functional expression of OX40 receptors on CD4+ T cells; 2) whether the OX40 receptor is required for effective communication between CD4+ T cells and B cells to generate potent antibody responses; and 3) whether B cell expression of the OX40 ligand is regulated by parasite byproducts and necessary for generating potent secreted antibody responses. Our proposed studies and new reagents provide tractable systems and a detailed framework for sustainable extensions of this project that will establish additional new paradigms for enhancing CD4+ T cell-mediated immunity against Plasmodium. Insight gained during the course of our studies will help us identify and develop new immune- based strategies to limit Plasmodium disease burden.

项目摘要 疟原虫感染和疾病疟疾仍然是全球健康的紧急情况。疟疾影响超过 去年有2亿人，造成近60万人丧生。靶向寄生虫的抗体反应对于 控制寄生虫复制并限制疟疾的严重程度。有效的抗体反应和最佳 刺激的B细胞需要CD4+ T细胞“帮助”。我们发表的工作表明CD4+ T细胞功能是 疟原虫感染后明显受损。我们将CD4+ T细胞的降低功能与 诱导共抑制受体表达，一类T细胞表面表达的蛋白质直接限制 CD4+ T细胞能够协调针对微生物病原体的保护性免疫反应。我们进一步 表明，在疟疾中阻止共抑制受体的活性恢复了CD4+ T细胞功能， 促进了强烈的抗体反应和受感染宿主的加速寄生虫控制和清除。 最近，我们确定我们还可以通过 激活OX40，这是一类T细胞刺激受体的成员。我们的新数据表明，在治疗上 在实验性质质子感染的第二周中刺激OX40受体的受体 抑制网络明显改善CD4+ T细胞活性和分泌的抗体反应，并限制 疟疾寄生虫复制。重要的是，我们还确定了感染恶性疟原虫的儿童的相似之处， 建立我们发现的相关性和意义，并加强科学前提 当前的建议。在这个项目中，我们应用新的细胞，遗传和寄生虫试剂来研究如何 OX40受体调节寄生虫特异性CD4+ T细胞与B细胞之间的通信以及 产生抗体反应。我们的科学问题和实验方法促进了我们的长期 定期目标是确定基于免疫的新方法，以刺激宿主抵抗 疟疾。我们的目标是由三个确定的特定目标来解决的：1） 疟原虫感染唯一调节了CD4+ T细胞上OX40受体的功能表达； 2） CD4+ T细胞和B细胞之间有效通信是否需要OX40受体 产生有效的抗体反应； 3）OX40配体的B细胞表达是否受到调节 寄生虫副产品，是产生有效的分泌抗体反应所必需的。我们提出的研究 新试剂提供可持续扩展的详细框架和详细的框架 将建立其他新范式来增强CD4+ T细胞介导的免疫力的项目 疟原虫。在我们的研究过程中获得的洞察力将有助于我们识别和发展新的免疫力 - 基于限制疟原虫疾病负担的策略。