REGULATION OF PROTECTIVE HUMORAL IMMUNITY TO STREPTOCOCCUS PNEUMONIAE BY PD-1

描述（由申请人提供）：本提案的目的是评估阻断PD-1免疫抑制受体及其配体之间相互作用的可行性，作为增强肺炎链球菌胶囊中发现的肺炎球菌多糖（PPSs）的保护性抗体反应的策略。肺炎链球菌继续构成全球威胁，是儿童发病和死亡的主要原因之一。PPS疫苗对成人血清型特异性侵袭性肺炎球菌疾病提供显著保护，但对非侵袭性疾病的保护效果较差，并且在非常年轻、老年人和免疫功能低下人群中激发保护性抗体反应的能力较差。了解如何调节对PPS的保护性抗体反应是设计更有效疫苗的关键。PPSs通常会引起T细胞独立的2型（TI-2）抗体反应，这种反应与抗体对蛋白质抗原的反应有明显的调节。我们之前发现，B细胞的一个独特亚群，称为B-1b细胞，在小鼠体内产生针对3型PPS （PPS-3）和其他TI-2抗原的抗体至关重要。我们的初步数据显示，抗原特异性B-1b细胞在TI-2抗原免疫后上调免疫抑制受体PD-1，阻断PD-1与其配体的相互作用可显著增加IgG对TI-2 Ags（包括PPS-3）的反应。尽管人们对开发pd -1相关的生物制剂和小分子抑制剂来治疗慢性病毒感染和恶性肿瘤有着浓厚的兴趣，但人们对这些疗法如何影响B细胞功能或宿主对细菌的防御知之甚少。本研究旨在探讨：1)抑制PD-1功能如何影响抗体对PPS-3反应的数量、持久性和保护能力；2)PD-1在多大程度上调节抗体对当前肺炎球菌疫苗中发现的不同类型PPS的反应；3)b细胞特异性PD-1表达在PPS抗体反应的调节中所起的作用。最后，由于PD-1仅在小鼠TI-2抗原免疫后在抗原特异性B-1b细胞上被显著诱导表达，我们将探索b -1样细胞在非人灵长类动物（非洲绿猴；AGM）中对TI-2抗体反应的功能贡献，以及PD-1类似调节这些细胞的潜力。这些探索性研究的结果将证明PD-1调控途径对肺炎链球菌保护性体液免疫产生的重要意义，并揭示B细胞特异性PD-1表达在小鼠这一过程中的重要性。最后，该项目将进一步发展AGM作为非人类灵长类动物的替代模型，以评估B细胞亚群和对PPS和其他临床相关TI-2抗原的抗体反应调节的因素。最终，这些研究可能会导致PD-1疗法的新应用，以增强基于pps的肺炎链球菌疫苗的疗效。

DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate the feasibility of blocking interactions between the PD-1 immunoinhibitory receptor and its ligands as a strategy to enhance protective antibody responses to pneumococcal polysaccharides (PPSs) found in the capsule of Streptococcus pneumoniae. S. pneumoniae continues to pose a global threat and is one of the leading causes of morbidity and mortality among children. PPS vaccines provide significant protection against serotype-specific invasive pneumococcal disease in adults, but are less efficacious against non-invasive disease and poorly stimulate protective antibody responses in very young, elderly, and immunocompromised populations. Understanding how protective antibody responses to PPS are regulated is key to devising more efficacious vaccines. PPSs typically elicit T cell independent type 2 (TI-2) antibody responses, which are regulated distinctly from antibody responses to protein antigens. We previously identified that a unique subset of B cells, termed B-1b cells, is critical for producing antibodies against type 3 PPS (PPS-3) and other TI-2 antigens in mice. Our preliminary data shows that antigen-specific B-1b cells upregulate the immunoinhibitory receptor PD-1 following TI-2 antigen immunization, and that blocking PD-1 from interacting with its ligands significantly increases IgG responses against TI-2 Ags, including PPS-3. Despite the intense interest in developing PD-1-related biologics and small molecule inhibitors for treatment of chronic viral infections and malignancies, very little is known about how these therapies may influence B cell function or host defense against bacteria. Studies in this proposal are designed to explore: 1) how inhibiting PD-1 function influences the quantity, persistence, and protective capacity of antibody responses to PPS-3, 2) the extent to which PD-1 regulates antibody responses to distinct types of PPS found in the current pneumococcal vaccine, and 3) the role B-cell-specific PD-1 expression plays in the regulation of PPS antibody responses. Finally, since PD-1 expression is only significantly induced on antigen-specific B-1b cells following TI-2 antigen immunization in mice, we will explore the functional contribution B-1-like cells make to TI-2 antibody responses in non-human primates (African Green monkeys; AGM) and the potential for PD-1 to similarly regulate these cells. The results of these exploratory studies will demonstrate the significance the PD-1 regulatory pathway has on the generation of protective humoral immunity to S. pneumoniae and will reveal the importance B cell-specific PD-1 expression plays in this process in mice. Finally, this project will further develop the AGM as an alternative non-human primate model in which to assess B cell subsets and factors contributing to the regulation of antibody responses against PPS and other clinically relevant TI-2 antigens. Ultimately, these studies may lead to new applications for PD-1 therapeutics in enhancing the efficacy of PPS-based vaccines against S. pneumoniae. PUBLIC HEALTH RELEVANCE: The goal of the research proposed in the current application is to understand how the immune system is regulated to respond to vaccines against Streptococcus pneumoniae. The knowledge gained from these studies may lead to improved vaccines that provide enhanced protection against pneumococcal infections currently threatening global public health.