The Germinal Center and T cell help in Three Phases of Clearance of Plasmodium

生发中心和 T 细胞帮助清除疟原虫的三个阶段

• 批准号: 10291407
• 负责人: Robin Stephens
• 金额: $ 17.05万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2022-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291407
• 关键词: Adjuvant; Affinity; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Appearance; B-Lymphocytes; Biological Assay; Biological Markers; Blocking Antibodies; Blood; CD4 Positive T Lymphocytes; Cell Communication; Cells; Cessation of life; Child; Chronic; Data; Development; Erythrocytes; Generations; Genetic; Goals; Growth; Helper-Inducer T-Lymphocyte; Human; Hybrids; Immune response; Immune system; Immunity; Immunoglobulin Class Switching; Infection; Infection Control; Interferon Type II; Knockout Mice; Knowledge; Malaria; Malaria Vaccines; Mediating; Modeling; Mus; Parasite Control; Parasitemia; Parasites; Pathologic; Pathology; Persons; Phase; Phenotype; Plasma Cells; Plasmablast; Plasmodium; Play; Production; Reaction; Regulation; Reporter; Risk; Role; Sorting - Cell Movement; Structure; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Work; cell type; cytokine; efficacy evaluation; experimental study; improved; in vivo; malaria infection; mouse model; novel; novel vaccines; response; translational potential; vaccine development; vaccine strategy; vaccine-induced immunity

ABSTRACT Despite improvements in infection control, one child dies every minute from malaria, which is caused by infection by Plasmodium parasites. Children develop immunity to malaria slowly after multiple exposures, and lose immunity in the absence of continuous exposure. A lack of critical knowledge about the antibody response that controls this infection hinders vaccine development. Early IFN-γ from Th1 cells limits early parasite growth and correlates with protection. CD4 T helper cells (Th) also promote parasite-specific antibody, which we have proposed is primarily required for full parasite clearance, which takes over a month. IL-21 promotes B cell responses and is also required for clearance of Plasmodium. Splenic germinal centers optimize B:T cell interactions that promote isotype switching and affinity maturation of antibodies, and long-lived plasma cell generation. However, the appearance of GCs is delayed until late in infection by the Th1 response. This slow response may explain the delay of development of immunity observed in the field. However, there is a significant extrafollicular antibody response that is faster, and actually corresponds with dramatic control of the parasite. In addition, our preliminary data showing that knockout mice lacking germinal centers (GC) control infection, led us to develop a working model of protection consisting of three phases. First, Th1 cytokines limit parasite growth; next, GC-independent factors control the parasite to low, but chronic levels without pathology; when finally, GCs play a role in complete clearance. Yet, the types of Th cells required, and the dominant mechanisms of antibody-mediated parasite killing are not yet clear, especially in the control phase. The role of IL-21 in an extrafollicular response has not been sufficiently studied to understand the mechanisms or importance. Therefore, we hypothesize that GC-independent mechanisms driven by IL-21 make a significant contribution to the control of Plasmodium infection. To test this, in Aim 1, we will compare the contribution of GCs and IL-21 for control of parasite. We will determine the importance of GC-driven antibody changes by using novel mouse models separately deficient in isotype switching and affinity maturation. There are also important unanswered questions about the type of Th cells that help B cells make antibody in malaria infection. We and others have recently discovered that the effector T helper cell response to mouse and human malaria is composed largely of a hybrid IFN-γ+ IL-21+ Th1/Tfh cell type that has all the hallmarks of both Th1 and Tfh. While IFN-γ was recently shown to inhibit GC formation, the role of hybrid IFN-γ+/IL-21+ T cells' contribution to antibody production in vivo, and their role in protection from parasitemia and pathology in malaria, have not been tested. Therefore, In Aim 2 we will evaluate the efficacy of hybrid IFN-γ+/IL-21+ Th1/Tfh in protection, by sorting them using cytokine reporter mice, and determine the phases of infection where IL-21 is critical. Understanding the mechanisms of both the control phase and final clearance is critical because control of parasite corresponds with termination of malaria pathology and may suggest novel vaccine strategies.

抽象的 尽管感染控制有所改善，但一个孩子每分钟都死于疟疾，这是由 寄生虫感染。多次暴露后，儿童对疟疾的免疫力缓慢，并且 在没有连续暴露的情况下失去免疫力。缺乏有关抗体反应的批判性知识 控制这种感染会阻碍疫苗的发育。来自Th1细胞的早期IFN-γ限制了早期寄生虫生长 并与保护相关。 CD4 T辅助细胞（Th）还促进了寄生虫特异性抗体，我们已经具有 提议的主要寄生虫清除主要是需要一个月的时间。 IL-21促进B细胞 响应，也是清除疟原虫所必需的。脾生发中心优化B：T细胞 促进抗体和长期血浆细胞的同种型切换和亲和力成熟的相互作用 一代。但是，TH1反应在感染后延迟GC的出现延迟。这很慢 反应可能解释了在现场观察到的免疫发育的延迟。但是，有一个 更快的速度外抗体反应，实际上与对 寄生虫。此外，我们的初步数据表明缺乏生发中心（GC）控制的敲除小鼠 感染，使我们开发了一个由三个阶段组成的保护模型。首先，Th1细胞因子极限 寄生虫生长；接下来，与GC无关的因素将寄生虫控制为低但没有病理的慢性水平。 最后，GCS在完全清除中发挥了作用。然而，所需的TH细胞类型和主要 抗体介导的寄生虫杀死的机制尚不清楚，尤其是在控制阶段。 IL-21在外面反应中的作用尚不完全研究，以了解机制或 重要性。因此，我们假设IL-21驱动的与GC无关的机制使得 对控制疟原虫感染的贡献。为了测试这一点，在AIM 1中，我们将比较 GCS和IL-21用于控制寄生虫。我们将确定通过GC驱动的抗体变化的重要性 使用新颖的小鼠模型分别缺乏同种型切换和亲和力成熟。也有 关于帮助B细胞在疟疾感染中导致抗体的TH细胞类型的重要问题。 我们和其他人最近发现，效应助理细胞对小鼠和人类疟疾的反应 主要由具有TH1和TFH的所有标志的杂种IFN-γ+ IL-21+ TH1/TFH细胞类型组成。 虽然最近显示IFN-γ抑制GC的形成，但混合IFN-γ+/IL-21+ T细胞对 体内抗体的产生及其在保护免受寄生虫病和疟疾病理学中的作用，尚未 经过测试。因此，在AIM 2中，我们将评估混合IFN-γ+/IL-21+ TH1/TFH在保护中的效率， 使用细胞因子报道小鼠对它们进行排序，并确定IL-21至关重要的感染阶段。 了解控制阶段和最终清除的机制至关重要，因为控制 寄生虫与疟疾病理学的终止相对应，并可能表明新型的疫苗策略。