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：
8806523
负责人：
Eva V Acosta Rodriguez
金额：
$ 13.34万
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/8806523
关键词：
Address Adoptive Transfer Affect Area B-Lymphocytes Back Biology CD4 Positive T Lymphocytes CD8B1 gene Cell Maintenance Cells Chagas Disease Chronic Collaborations Country Cues Cytokine Signaling Data Dendritic Cells Development Disease Progression Economic Burden Elements Frequencies Generations Goals Health Heterogeneity Host resistance Human Immune response Immunity Immunization Immunology In Vitro Indium 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 cell response T-Cell Development T-Lymphocyte Testing Therapeutic Effect Therapeutic Uses Trypanosoma cruzi Vaccination Vaccine Design Vaccines Work adaptive immunity base cytokine design exhaust experience functional genomics genetic vaccine human disease improved insight mortality novel therapeutics pathogen programs public health relevance research study 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）：由Cruzi寄生虫造成的Chagas疾病影响800万人，并由于早期死亡率和身体残疾而造成了重大的经济负担。它在拉丁美洲是地方性的，但在非流行国家中的病例正在增加，成为全球关注的问题。疾病的进展从无症状到严重，与寄生虫异质性和可变宿主免疫反应有关。实际上，强大的CD8+ T细胞免疫的发展是宿主抗性的关键要素，而Cruzi持久性和慢性Chagas疾病与次优的CD8+ T细胞反应有关。因此，定义介导免疫保护的CD8+ T细胞的性质和管理这些细胞维持的规则对于我们对Chagas疾病发病机理的理解以及新型治疗和疫苗接种方法的设计至关重要。细胞因子是中央环境线索，它决定了保护性CD8+ T细胞反应的幅度和质量，因此成为免疫干预的有吸引力的靶标。但是，我们对最佳CD8+ T细胞免疫产生的细胞因子，信号途径和转录程序的不完整知识使可能与人类健康相关的可能应用。我们引人注目的初步发现表明，IL-17RA信号细胞因子与确定可靠的保护性CD8+ T细胞对T. cruzi的稳健保护性CD8+ T细胞反应的发育途径的调节至关重要。使用表型，功能和基因组分析，我们建议剖析特定CD8+ T细胞发育的IL-17RA介导的调节基础的机制。收养转移实验以及体外培养方法将用于确定IL-17RA信号是否在支持CD8+ T细胞免疫方面发挥CD8+ T细胞的固有和/或外部作用。最后，遗传疫苗接种和基于细胞因子的治疗将有助于确定在自然感染和疫苗接种期间，IL-17A的潜在治疗用途增强CD8+ T细胞对Cruzi的免疫。我们的研究将提供有关IL-17RA信号细胞因子在调节CD8+ T细胞对T. Cruzi的免疫中的作用的有意义的数据，从而为Chagas疾病的理性设计提供了潜在的新靶标，并且很可能是其他慢性感染。我们还期望确定由IL-17RA信号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。这些知识将对基本免疫学产生深远的影响，并可能为理解人类疾病中IL-17靶向疗法的无引起的影响提供理由。