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

抗体分泌细胞调节 T 细胞对克氏锥虫的反应

• 批准号: 9058981
• 负责人: ADRIANA GRUPPI
• 金额: $ 13.31万
• 依托单位: NATIONAL RESEARCH COUNCIL OF ARGENTINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058981
• 关键词: Acute; Affect; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigens; Attenuated; Autoimmune Process; B-Cell Activation; B-Lymphocytes; Bacteria; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell physiology; Cells; Chagas Disease; Characteristics; Chimera organism; Chronic; Clinic; Clinical; Coculture Techniques; Cultured Cells; Data; Development; Disease; Disease Progression; Economic Burden; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Frequencies; Functional disorder; Generations; Genetic; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Host Defense; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin-Secreting Cells; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-17; Knowledge; Latin America; Life; Ligands; Link; Location; Longevity; Lymphocyte; MHC Class II Genes; Malignant Neoplasms; Mediator of activation protein; Membrane Proteins; Microbe; Modification; Mus; Nature; Organ; PDCD1LG1 gene; Parasitemia; Parasites; Pathogenesis; Pathway interactions; Phase; Phenotype; Physically Handicapped; Plasma Cells; Plasmablast; Play; Population; Production; Property; Public Health; Regulation; Reporting; Role; Salmonella infections; Signal Pathway; Signal Transduction; Source; Spleen; Structure of germinal center of lymph node; T cell response; T-Cell Activation; T-Lymphocyte; TNF gene; Tissues; Trans-Activators; Trypanosoma cruzi; Up-Regulation; adaptive immunity; antimicrobial; cytokine; design; differentiated B cell; expectation; fight against; in vivo; microbial; microorganism; migration; mortality; novel; novel therapeutic intervention; novel therapeutics; parasitism; pathogen; programs; research study; response; therapeutic target; tool; tumor progression

 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.

 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，但可能由于受感染者的迁移而成为全球公共卫生问题。疾病的进展，从轻微到严重，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症免疫反应的强度是该疾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，但当失调时，它可能导致持续的组织损伤和器官功能障碍。因此，确定能够维持宿主完整性以及病原体复制的细胞和分子的性质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，查加斯病的急性期以免疫抑制状态为标志，在这种状态下，T。cruzi广泛复制并诱导延迟寄生虫特异性T细胞应答的免疫调节分子。这种T细胞状态与多克隆B细胞活化共存，表明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，主要以其分泌抗体的独特能力而闻名。值得注意的是，最近的研究确定抗体分泌细胞（ASC）作为产生抗炎细胞因子的活化B细胞的主要类型，因此为它们提出了调节细胞的新作用。在本研究中，我们将研究T.克氏感染我们将特别研究由显示PD-L1的均匀高表达的感染引起的ASC（PD-L1 hi ASC）是否能够调节T细胞应答。通过基因修饰小鼠、共培养实验和混合骨髓嵌合体实验，研究PD-L1 hi ASC的特性及其在T.克氏感染通过对参与几种信号传导途径的分子进行遗传修饰并通过细胞培养试验感染小鼠，我们将评估参与PD-L1 hi ASC生成的信号、细胞内途径和转录程序。鉴定调节性浆细胞的表型和寿命特征对于开发针对治疗性浆细胞的新策略具有重要意义。 在临床上靶向B细胞。例如，这些知识可以帮助开发新的工具来选择性地消耗那些负调节T细胞应答的ASC，而不影响在感染中起保护作用的高亲和力ASC。