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，但每分钟就有一名儿童死于疟疾，疟疾是由疟疾引起的 疟原虫寄生虫感染。多次接触疟疾后，儿童会慢慢形成对疟疾的免疫力，并且 如果没有持续接触，就会失去免疫力。缺乏有关抗体反应的关键知识 控制这种感染的方法阻碍了疫苗的开发。 Th1 细胞的早期 IFN-γ 限制了早期寄生虫的生长 并与保护相关。 CD4 T 辅助细胞 (Th) 也会促进寄生虫特异性抗体，我们已发现 提议的主要需要完全清除寄生虫，这需要一个多月的时间。 IL-21促进B细胞 反应，也是清除疟原虫所必需的。脾脏生发中心优化 B:T 细胞 促进抗体同种型转换和亲和力成熟以及长寿浆细胞的相互作用 一代。然而，GC 的出现被 Th1 反应延迟到感染晚期。这慢 反应可以解释在现场观察到的免疫力发展延迟的原因。然而，有一个 显着的滤泡外抗体反应更快，并且实际上与对滤泡的显着控制相对应 寄生虫。此外，我们的初步数据显示，缺乏生发中心（GC）控制的基因敲除小鼠 感染，导致我们开发了一个由三个阶段组成的保护工作模型。一、Th1细胞因子限制 寄生虫生长；其次，不依赖 GC 的因素将寄生虫控制在较低但慢性的水平，且没有病理变化； 最后，GC 发挥完全清除的作用。然而，所需的 Th 细胞类型以及占主导地位的 抗体介导的寄生虫杀灭机制尚不清楚，特别是在控制阶段。这 IL-21 在卵泡外反应中的作用尚未得到充分研究以了解其机制或 重要性。因此，我们假设 IL-21 驱动的 GC 独立机制在 为控制疟原虫感染做出贡献。为了测试这一点，在目标 1 中，我们将比较 GC 和 IL-21 用于控制寄生虫。我们将通过以下方式确定 GC 驱动的抗体变化的重要性 使用分别缺乏同种型转换和亲和力成熟的新型小鼠模型。还有 有关在疟疾感染中帮助 B 细胞产生抗体的 Th 细胞类型的重要未解答问题。 我们和其他人最近发现效应 T 辅助细胞对小鼠和人类疟疾的反应 主要由混合型 IFN-γ+ IL-21+ Th1/Tfh 细胞类型组成，具有 Th1 和 Tfh 的所有特征。 虽然 IFN-γ 最近被证明可以抑制 GC 形成，但混合 IFN-γ+/IL-21+ T 细胞在抑制 GC 形成中的作用 体内抗体的产生，以及它们在预防疟疾寄生虫血症和病理学方面的作用，尚未 经测试。因此，在目标 2 中，我们将评估混合 IFN-γ+/IL-21+ Th1/Tfh 的保护功效，方法是 使用细胞因子报告小鼠对它们进行分类，并确定 IL-21 发挥关键作用的感染阶段。 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，并可能提出新的疫苗策略。