Maintenance vs Programming in Th1 Memory Cell Development in P. Chabaudi Malaria

P. Chabaudi 疟疾中 Th1 记忆细胞发育的维护与编程

• 批准号: 8287524
• 负责人: Robin Stephens
• 金额: $ 34.35万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287524
• 关键词: Accounting; Address; Affect; Antigens; B-Lymphocytes; Biological Assay; Cell Maintenance; Cells; Cellular Immunity; Cessation of life; Chromatin; Chromatin Remodeling Factor; Chronic; Chronic Disease; Commit; Complement; Culicidae; Cytokine Receptors; Data; Development; Disease; Drug resistance; Flow Cytometry; Genetic Transcription; Goals; HIV; Hand functions; Hepatitis C; Human; Humanities; Immune system; Immunity; Immunologic Techniques; Immunology; Infection; Inflammation; Interferons; Knowledge; Life; Literature; Longevity; Maintenance; Malaria; Measurable; Memory; Merozoite Surface Protein 1; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Parasites; Pattern; Phase; Phenotype; Plague; Planet Mars; Plasmodium chabaudi; Population; Prevention strategy; Production; Protocols documentation; Research; Resistance development; Speed; Stimulus; Symptoms; System; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Th1 Cells; Transgenic Organisms; Tuberculosis; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; Work; burden of illness; cell type; cytokine; flexibility; in vitro testing; in vivo; innovation; insight; killings; memory CD4 T lymphocyte; novel; pathogen; pesticide resistance; programs; research study; response; treatment strategy; vaccination against tuberculosis; vaccine development

DESCRIPTION (provided by applicant): Two major hurdles in developing effective vaccines for chronic infections such as HIV, TB and malaria are the lack of knowledge of the critical factors for maintenance of protective immunity, and the lack of a measurable cell type that correlates with protection. To address these gaps in our knowledge, we propose to identify the protective memory T cell subsets in chronic malaria infection and define the mechanisms that they use to survive and maintain protective cytokine production. Our preliminary data demonstrate that malaria- specific T cells differentiate into effector memory cells (Tem), which contribute to protection best if they are exposed to chronic infection. Chronic infection also enhances their Th1 cytokine production (IFN3+), correlating with this protection. Therefore, our central hypothesis is that Tem subsets maintain a protective cytokine program like committed Th1 cells that is maintained by the inflammation associated with chronic infection. The goals of this proposal are therefore to determine which CD4+ memory T cell subsets are protective and survive and which help B cells (T follicular helper, Tfh) or remain committed to the Th1 phenotype. These goals will be achieved by the completion of the following specific aims: 1) To determine protection, survival and effector function (Th1, Tfh) of CD4+ effector memory T cell subsets, and 2) To determine subsets producing IFN3 and their degree of Th1 commitment. The first aim will define protective memory T cell subsets and the factors required for their maintenance and will be accomplished by in vivo protection, survival and cytokine production assays already established as feasible in the applicant's hands, using modern in vivo immunological techniques and multi-parameter flow cytometry. The second aim is firstly to test the in vitro stability of the Th1 cytokine profile of malaria-specific memory cells, using the same techniques I used in my dissertation work, and secondly; to study the indicative pattern of cytokines, cytokine receptors, transcription and chromatin tatistics factors to define mechanisms utilized by Th1 memory cells for maintenance of their effector function in chronic infection. The outcomes of these two aims will allow us to define stimuli used by protective memory CD4+ T cells to survive and the mechanisms to remain protective in chronic infection. Providing knowledge including both novel stimuli to include for a successful vaccination protocol and a memory T cell- type that correlates with protection. The approach is innovative because we have a novel malaria-specific T cell transgenic system, an accurate murine malaria model, using Plasmodium chabaudi; and also because the proposal focuses on effector memory T cells, though others have disregarded them in favor of central memory cells, in spite of evidence of better protection by Tem. This approach to vaccination is supported by evidence that generating and maintaining effector memory cells by vaccination is feasible. The proposed research is significant because the outcomes are directly applicable to malaria, HIV and TB vaccination trials and may speed the search for a protective vaccine to malaria, one of the most lethal infections of mankind.

描述(申请人提供)：开发针对艾滋病毒、结核病和疟疾等慢性感染的有效疫苗的两大障碍是缺乏对维持保护性免疫的关键因素的了解，以及缺乏与保护相关的可测量的细胞类型。为了解决我们知识中的这些差距，我们建议确定慢性疟疾感染中的保护性记忆T细胞亚群，并定义它们用于生存和维持保护性细胞因子产生的机制。我们的初步数据表明，疟疾特异性T细胞分化为效应记忆细胞(Tem)，如果它们暴露在慢性感染中，效果记忆细胞(Tem)的保护作用最好。慢性感染也增加了他们Th1细胞因子的产生(IFN3+)，与这种保护相关。因此，我们的中心假设是，Tem亚群维持一个保护性的细胞因子程序，就像承诺的Th1细胞一样，由与慢性感染相关的炎症维持。因此，这项建议的目标是确定哪些CD4+记忆T细胞亚群具有保护性并存活下来，哪些有助于B细胞(T滤泡辅助者，TFH)或保持Th1表型。这些目标将通过完成以下具体目标来实现：1)确定CD4+效应记忆T细胞亚群的保护、存活和效应功能(Th1，Tfh)；2)确定产生IFN3的亚群及其Th1承诺的程度。第一个目标将定义保护性记忆T细胞亚群及其维持所需的因素，并将通过已经在申请人手中确立为可行的体内保护、存活和细胞因子产生分析来实现，使用现代体内免疫学技术和多参数流式细胞术。第二个目的是首先使用我在论文工作中使用的相同技术来测试疟疾特异性记忆细胞Th1细胞因子谱的体外稳定性，其次研究细胞因子、细胞因子受体、转录和染色质统计因子的指示模式，以确定Th1记忆细胞在慢性感染中维持其效应功能的机制。这两个目标的结果将使我们能够定义保护性记忆CD4+T细胞用于生存的刺激，以及在慢性感染中保持保护性的机制。提供包括用于成功接种疫苗方案的新刺激和与保护相关的记忆T细胞类型的知识。这种方法是创新的，因为我们有一个新的疟疾特异性T细胞转基因系统，一个准确的小鼠疟疾模型，使用查鲍迪疟原虫；还因为该提案侧重于效应器记忆T细胞，尽管其他人忽略了它们，转而支持中央记忆细胞，尽管有证据表明Tem具有更好的保护作用。有证据表明，通过接种来产生和维持效应记忆细胞是可行的，这支持了这种接种方法。这项拟议的研究意义重大，因为其结果直接适用于疟疾、艾滋病毒和结核病疫苗接种试验，并可能加速寻找疟疾的保护性疫苗，疟疾是人类最致命的感染之一。