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IL-17RA-signaling cytokines in the regulation of CD8 T cell immunity to T. cruzi

IL-17RA 信号细胞因子在调节 CD8 T 细胞对克氏锥虫的免疫中的作用

基本信息

批准号：
9228301
负责人：
Eva V Acosta Rodriguez
金额：
$ 13.36万
依托单位：
NATIONAL RESEARCH COUNCIL OF ARGENTINA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228301
关键词：
Address Adoptive Transfer Affect Area B-Lymphocytes Back Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Maintenance Cells Chagas Disease Chronic Collaborations Country Cues Cytokine Signaling Data Dendritic Cells Development Disease Progression Economic Burden Elements Frequencies Generations Genetic Transcription Goals Health Heterogeneity Host resistance Human Immune response Immunity Immunization Immunology In Vitro Infection Interleukin-17 Knowledge Latin America Link Maintenance Mediating Memory Molecular Mouse Strains Mus Nature Parasites Pathogenesis Pathway interactions Phenotype Physically Handicapped Play Recombinant Proteins Recombinants Regulation Regulatory T-Lymphocyte Reporting Research Role Shapes Signal Pathway Signal Transduction Site T-Lymphocyte Testing Therapeutic Effect Therapeutic Uses Trypanosoma cruzi Vaccination Vaccine Design Vaccines adaptive immune response base cytokine design exhaust experience experimental study functional genomics genetic vaccination genomic profiles human disease improved insight mortality novel therapeutics pathogen programs public health relevance response success targeted treatment therapy design

项目摘要

DESCRIPTION (provided by applicant): Chagas disease, caused by the parasite Trypanosoma cruzi, affects 8 million people and imposes a major economic burden due to early mortality and physical disabilities. It is endemic in Latin America but cases are increasing in non-endemic countries, becoming a global concern. Disease progression, from symptomless to severe, are linked to parasite heterogeneity and variable host immune response. Indeed, development of robust CD8+ T cell immunity is a key element of host resistance and T. cruzi persistence and chronic Chagas disease has been associated to suboptimal CD8+ T cell responses. Consequently, defining the nature of CD8+ T cells mediating immunoprotection and the rules governing the maintenance of these cells is crucial for our understanding of the pathogenesis of Chagas disease and also for the design of novel therapeutic and vaccination approaches. Cytokines are central environmental cues that dictate the magnitude and quality of protective CD8+ T cell responses and, thus, emerge as attractive targets for immunointervention. However, our incomplete knowledge about the cytokines, signaling pathways and transcriptional programs involved in the generation of optimal CD8+ T cell immunity holds back possible applications of relevance to human health. Our compelling preliminary findings show that IL-17RA-signaling cytokines are critically involved in the regulation of the developmental pathways that determine the generation of robust protective CD8+ T cell responses to T. cruzi. Using phenotypic, functional and genomic profiling we propose to dissect the mechanisms underlying IL-17RA-mediated regulation of specific CD8+ T cell development. Adoptive transfer experiments together with in vitro culture approaches will be used to establish whether IL-17RA-signaling plays CD8+ T cell intrinsic and/or extrinsic roles in supporting CD8+ T cell immunity. Finally, genetic vaccination and cytokine-based treatment will help to determine the potential therapeutic use of IL-17A to boost CD8+ T cell immunity to T. cruzi during natural infection and vaccination. Our studies will provide meaningful data about the role of IL-17RA-signaling cytokines in the regulation of CD8+ T cell immunity to T. cruzi, providing potential new targets for the rational design of therapies for Chagas disease and, likely, other chronic infections. We also expect to identify the cellular and molecular programs triggered by IL-17RA-signaling and how they dictate particular CD8+ T cell fates. This knowledge will profoundly impact on fundamental immunology and may provide a rationale for understanding unsuspected effects of IL-17-targeted therapies during human diseases.

描述（由申请人提供）：恰加斯病由寄生虫克氏锥虫引起，影响 800 万人，并因过早死亡和身体残疾而造成重大经济负担。它在拉丁美洲流行，但非流行国家的病例正在增加，成为全球关注的问题。疾病进展，从无症状到严重，与寄生虫异质性和可变的宿主免疫反应有关。事实上，强大的 CD8+ T 细胞免疫的发展是宿主抵抗力的关键因素，克氏锥虫的持久性和慢性恰加斯病与欠佳的 CD8+ T 细胞反应有关。因此，定义介导免疫保护的 CD8+ T 细胞的性质以及控制这些细胞维持的规则对于我们了解恰加斯病的发病机制以及设计新的治疗和疫苗接种方法至关重要。细胞因子是决定保护性 CD8+ T 细胞反应的程度和质量的核心环境线索，因此成为免疫干预的有吸引力的目标。然而，我们对产生最佳 CD8+ T 细胞免疫所涉及的细胞因子、信号通路和转录程序的了解不完全，阻碍了与人类健康相关的可能应用。我们令人信服的初步研究结果表明，IL-17RA 信号细胞因子关键参与发育途径的调节，从而决定对克氏锥虫产生强大的保护性 CD8+ T 细胞反应。我们建议使用表型、功能和基因组分析来剖析 IL-17RA 介导的特定 CD8+ T 细胞发育调节的机制。过继转移实验与体外培养方法将用于确定 IL-17RA 信号传导是否在支持 CD8+ T 细胞免疫方面发挥 CD8+ T 细胞内在和/或外在作用。最后，基因疫苗接种和基于细胞因子的治疗将有助于确定 IL-17A 在自然感染和疫苗接种过程中增强 CD8+ T 细胞对克氏锥虫的免疫的潜在治疗用途。我们的研究将提供关于 IL-17RA 信号细胞因子在调节克氏锥虫 CD8+ T 细胞免疫中的作用的有意义的数据，为恰加斯病和可能的其他慢性感染的合理设计疗法提供潜在的新靶点。我们还期望确定由 IL-17RA 信号传导触发的细胞和分子程序以及它们如何决定特定的 CD8+ T 细胞命运。这些知识将对基础免疫学产生深远影响，并可能为理解 IL-17 靶向疗法在人类疾病期间意想不到的作用提供依据。