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

描述（由申请人提供）：查加斯病由寄生虫克氏锥虫引起，影响800万人，并由于早期死亡和身体残疾而造成重大经济负担。它在拉丁美洲流行，但在非流行国家病例正在增加，成为全球关注的问题。疾病进展，从轻微到严重，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CD 8 + T细胞免疫的发展是宿主抗性和T. cruzi持续性和慢性恰加斯病与次优的CD 8 + T细胞应答相关。因此，定义介导免疫保护的CD 8 + T细胞的性质和管理这些细胞的维持的规则对于我们理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CD 8 + T细胞应答的大小和质量的中心环境因子，因此成为免疫干预的有吸引力的靶点。然而，我们对细胞因子、信号传导途径和转录程序的不完整了解阻碍了与人类健康相关的可能应用，这些细胞因子、信号传导途径和转录程序参与产生最佳的CD 8 + T细胞免疫。我们令人信服的初步研究结果表明，IL-17 RA信号细胞因子在发育途径的调节中起着至关重要的作用，这些发育途径决定了对T细胞产生强大的保护性CD 8 + T细胞应答。克鲁兹使用表型，功能和基因组分析，我们建议解剖的机制，IL-17 RA介导的特定的CD 8 + T细胞发育的调节。连续转移实验与体外培养方法一起将用于确定IL-17 RA信号传导在支持CD 8 + T细胞免疫中是否发挥CD 8 + T细胞内在和/或外在作用。最后，基因疫苗接种和基于精氨酸的治疗将有助于确定IL-17 A在增强CD 8 + T细胞对T细胞免疫方面的潜在治疗用途。在自然感染和接种疫苗期间。我们的研究将为IL-17 RA信号细胞因子在调节CD 8 + T细胞对T细胞免疫中的作用提供有意义的数据。cruzi，为合理设计恰加斯病和其他慢性感染的治疗方法提供了潜在的新靶点。我们还希望确定由IL-17 RA信号转导触发的细胞和分子程序，以及它们如何决定特定的CD 8 + T细胞命运。这些知识将对基础免疫学产生深远的影响，并可能为理解IL-17靶向治疗在人类疾病中的意外作用提供理论基础。

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.