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

描述（由申请人提供）：恰加斯病由克氏锥虫寄生虫引起，影响800万人，由于早期死亡和身体残疾造成重大经济负担。它在拉丁美洲流行，但在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，与寄生虫异质性和宿主免疫反应的变化有关。事实上，强大的CD8+ T细胞免疫的发展是宿主抵抗的关键因素，克氏锥虫的持久性和慢性恰加斯病与次理想的CD8+ T细胞反应有关。因此，确定介导免疫保护的CD8+ T细胞的性质和控制这些细胞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CD8+ T细胞反应的大小和质量的中心环境线索，因此成为免疫干预的有吸引力的靶点。然而，我们对产生最佳CD8+ T细胞免疫的细胞因子、信号通路和转录程序的不完全了解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信号细胞因子在发育途径的调节中起着关键作用，这些发育途径决定了CD8+ T细胞对T. cruzi产生强大的保护性反应。利用表型、功能和基因组分析，我们建议剖析il - 17ra介导的特异性CD8+ T细胞发育调控的机制。过继性转移实验和体外培养方法将用于确定il - 17ra信号是否在支持CD8+ T细胞免疫中发挥CD8+ T细胞内在和/或外在的作用。最后，基因疫苗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细胞对克氏锥虫免疫的潜在治疗用途。我们的研究将提供有关il - 17ra信号细胞因子在调节CD8+ T细胞对克氏锥虫免疫中的作用的有意义的数据，为合理设计恰加斯病和其他可能的慢性感染的治疗方法提供潜在的新靶点。我们还希望确定由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。这一知识将对基础免疫学产生深远的影响，并可能为理解人类疾病期间il -17靶向治疗的未预料到的作用提供理论依据。

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.