Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease

项目总结/摘要 南美锥虫病是由原生动物克氏锥虫引起的，在拉丁美洲是地方性的， 在非流行性国家增加，成为全球关注的问题。它影响了600万人， 由于过早死亡和身体残疾造成的重大经济负担。疾病进展，从无症状 严重的，与寄生虫异质性和可变的宿主免疫反应有关。发展强有力的 CD 8 + T细胞免疫是宿主抵抗和T.克氏持续病和慢性恰加斯病 与次优的CD 8 + T细胞应答相关。尽管如此， 促进对T细胞的强保护性CD 8 + T细胞免疫。cruzi仍然不完整，例如，代谢 效应CD 8 + T细胞在扩增和分化中所面临的障碍几乎没有被探索。还 T的进展。Cruzi感染被认为受到调节性免疫应答的显著调节， 限制寄生虫特异性免疫以及感染相关的免疫病理学机制差 明白在这种情况下，定义效应和调节途径如何交织在一起，以允许产生 最佳的细胞免疫力。克氏保存组织内稳态对于了解南美锥虫病至关重要 发病机理在这个方向上，我们发表的数据显示Treg细胞在T. Cruzi感染并获得了沿着感染而显著改变的表型属性。Treg细胞 获得性特征与1型反应的调节和有限的CD 8 + T细胞免疫有关， 感染急性期，可能延迟寄生虫控制和有利于慢性化。相比之下，初步数据 表明在急性期不受欢迎的具有组织修复联系的Treg细胞在急性期积累， 在慢性期，T. cruzi和减少组织损伤。 总之，我们的研究结果突出了表型和功能概况以及主要功能的许多变化。 在从急性期到慢性期的过渡中，特化Treg细胞的位置，表明Treg细胞的作用 在感染过程中从有害转变为保护。一个全面的表征， Treg细胞在不同组织中的表型、功能和转录程序，以及 通过不同的策略操纵这个调节子集将使我们能够定义潜在的机制， Treg细胞介导的急性和慢性实验性T细胞效应免疫和免疫病理学调节。 克氏感染这些方法将指导我们对效应和调节途径及其相关性的评估。 与慢性恰加斯病患者样本中临床严重程度的相关性，以将我们的 发现对人体健康。总之，我们的研究将提供有意义的数据， 途径，并可能，新的介质，参与调节效应细胞免疫T。cruzi 和慢性病理学的发展。这些信息将确定潜在的新目标， 设计治疗南美锥虫病和其他慢性感染的方法。

PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America but cases are increasing in non-endemic countries, becoming a global concern. It affects 6 million people and imposes a major economic burden due to early mortality and physical disabilities. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. 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. Despite this, the knowledge about pathways that promote robust protective CD8+ T cell immunity to T. cruzi remains incomplete and for instance, the metabolic hurdles faced by effector CD8+ T cells for expansion and differentiation have been barely explored. Also, the progression of T. cruzi infection is thought to be significantly modulated by regulatory immune responses that limit parasite-specific immunity as well as infection-associated immunopathology by mechanisms poorly understood. In this context, defining how effector and regulatory pathways intertwined to allow the generation of optimal cellular immunity against T. cruzi preserving of tissue homeostasis is crucial to understand Chagas disease pathogenesis. In this direction, our published data showed that Treg cells became activated during T. cruzi infection and acquired phenotypic attributes that markedly changed along the infection. Thus, Treg cells acquired features linked to the regulation of type 1 responses and limited CD8+ T cell immunity during the infection acute phase, likely delaying parasite control and favoring chronicity. In contrast, preliminary data demonstrate that Treg cells with tissue repair ties, which were disfavored during the acute phase, accumulated during the chronic phase in nonlymphoid tissues considered targets of T. cruzi and reduced tissue damage. Altogether, our findings highlight numerous changes in the phenotypic and functional profile as well as main location of specialized Treg cells in the transition from acute to chronic phase, suggesting that Treg cell roles switch from deleterious to protective in the course of this infection. A comprehensive characterization of phenotype, function and transcriptional program of Treg cells in different tissues, together with the manipulation of this regulatory subset by different strategies will allow us to define the mechanisms underlying Treg cell mediated regulation of effector immunity and immunopathology in acute and chronic experimental T. cruzi infection. These approaches will guide our evaluation of effector and regulatory pathways and their association to the clinical severity in samples of patients with chronic Chagas disease in order to translate our finding to human health. Altogether, our studies will provide meaningful data about different interacting pathways and, possibly, new mediators that participate in the regulation of effector cellular immunity to T. cruzi and the development of chronic pathology. This information will identify potential new targets for the rational design of therapies for Chagas´ disease and, likely, other chronic infections.