Regulation of Plasmodium-specific CD4+ T Cells

疟原虫特异性 CD4 T 细胞的调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概要疟原虫感染和疟疾仍然是全球卫生紧急情况。疟疾影响超过去年有2亿人死亡，近60万人死亡。针对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受刺激的 B 细胞需要 CD4+ T 细胞的“帮助”。我们发表的研究表明 CD4+ T 细胞功能疟原虫感染后明显受损。我们将 CD4+ T 细胞功能的降低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 细胞协调针对微生物病原体的保护性免疫反应的能力。我们进一步研究表明，在疟疾期间阻断共抑制受体的活性可恢复 CD4+ T 细胞功能，促进强烈的抗体反应并加速寄生虫控制和从受感染宿主中清除。最近，我们发现我们还可以通过以下方式恢复疟原虫特异性 CD4+ T 细胞的功能：激活 OX40，一类 T 细胞刺激受体的成员。我们的新数据表明，在治疗上在实验性疟原虫感染的第二周刺激 OX40 受体克服了共抑制网络，显着提高 CD4+ T 细胞活性和分泌抗体反应，并限制疟疾寄生虫的复制。重要的是，我们还在感染恶性疟原虫的儿童中发现了相似之处，确立我们的发现的相关性和意义，并加强我们的科学前提当前的提案。在这个项目中，我们应用新的细胞、遗传和寄生虫学试剂来研究 OX40 受体调节寄生虫特异性 CD4+ T 细胞和 B 细胞之间的通讯抗体反应的产生。我们的科学问题和实验方法促进了我们的长期长期目标是确定新的基于免疫的方法来刺激宿主抵抗疟疾。我们的目标由三个具体目标来实现，这些目标将决定：1）疟原虫感染独特地调节 CD4+ T 细胞上 OX40 受体的功能表达； 2） CD4+ T 细胞和 B 细胞之间的有效通讯是否需要 OX40 受体产生有效的抗体反应； 3) OX40配体的B细胞表达是否受调节寄生虫副产物，是产生有效的分泌抗体反应所必需的。我们提出的研究新的试剂提供了易于处理的系统和详细的框架，以可持续扩展这一领域该项目将建立额外的新范例，以增强 CD4+ T 细胞介导的免疫疟原虫。我们在研究过程中获得的见解将帮助我们识别和开发新的免疫系统基于限制疟原虫疾病负担的策略。