Antibody-secreting cells in the regulation of T cell response to Trypanosoma cruzi

 描述(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，但可能是由于感染者的迁徙而成为全球公共卫生问题。疾病的发展，从无症状到严重，与寄生虫的异质性和可变的宿主免疫反应有关。据报道，寄生虫的持久性以及炎性免疫反应的强度是该病临床表现的决定因素。尽管炎症对于宿主防御是不可或缺的，但当放松调控时，它可能会导致持续的组织损伤和器官功能障碍。因此，确定能够维持宿主S完整性的细胞和分子的性质以及病原体的复制对于我们理解恰加斯病的发病机制以及设计新的治疗方法至关重要。在小鼠和人类中，恰加斯病的急性期以免疫抑制状态为标志，在这种状态下，克氏锥虫大量复制，并诱导免疫调节分子，延迟寄生虫特异的T细胞反应。这种T细胞状态与多克隆B细胞激活共存，提示B细胞可以影响T细胞功能，反之亦然。终末分化的B细胞，即浆细胞，主要以其独特的抗体分泌能力而闻名。值得注意的是，最近的研究发现抗体分泌细胞(ASC)是产生抗炎细胞因子的主要激活B细胞类型，因此提出了调节细胞对它们的新作用。在这项建议中，我们将研究Asc在克氏毛滴虫感染中的抗体非依赖性功能。我们将特别研究由感染引起的、显示PD-L1(PD-L1hi ASC)一致高表达的ASC是否能够调节T细胞反应。通过转基因小鼠、共培养实验和混合骨髓嵌合体实验，我们将确定PD-L1hi ASC的特性及其在旋毛虫感染中的作用。通过感染小鼠，通过几个信号通路中涉及的分子的遗传修饰和细胞培养试验，我们将评估参与PD-L1hi ASC生成的信号、细胞内途径和转录程序。识别调控浆细胞的表型和寿命特征对于开发针对治疗的新策略具有重要意义。 B细胞在临床上的靶向。例如，这些知识可以帮助开发新的工具，有选择地耗尽那些负面调节T细胞反应的ASC，而不影响在感染中发挥保护作用的高亲和力ASC。

 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 became a global public health concern possibly by migration of infected people. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to continuous tissue injury and organ dysfunction. Consequently, defining the nature of cells and molecules able to maintain the host s integrity as well as the pathogen replication is crucial for our understanding of the pathogenesis of Chagas disease and also for the design of novel therapeutic approaches. The acute phase of Chagas disease in mice and humans is marked by a state of immunosuppression in which T. cruzi replicates extensively and induces immune- modulatory molecules that delay parasite-specific T cell responses. This T cell status coexists with polyclonal B cell activation, suggesting that B cells can influence T cell function and vice versa. Terminally differentiated B cells, the plasma cells, have been primarily known for their unique capacity to secrete antibodies. Remarkably, recent studies identified antibody-secreting cells (ASC) as the main type of activated B cells which produce anti-inflammatory cytokines and so a new role of regulatory cells was proposed for them. In this proposal we will study the Ab-independent function of ASC in T. cruzi infection. We will particularly investigate whether ASC elicited by the infection that show a uniformly high expression of PD-L1 (PD-L1hi ASC) are able to condition T cell responses. By using genetically-modified mice, co-culture experiments and mixed bone marrow chimeras we will determine the characteristic of PD-L1hi ASC and their function in T. cruzi infection. By infection of mice with genetic modifications in molecules involved in several signaling pathways and by cell culture assays, we will evaluate the signals, intracellular pathways and transcriptional programs involved in the generation of PD-L1hi ASC. The identification of the phenotypic and longevity features that characterize regulatory plasma cells will be of great significance for the development of new strategies aiming at the therapeutic targeting of B cells in the clinic. For instance, such knowledge could help to develop novel tools to selectively deplete those ASC that negatively regulate T cell response without affecting high affinity ASC which play a protective role in infections.