T follicular regulatory cells, a potential HIV reservoir.

滤泡调节 T 细胞，一个潜在的 HIV 储存库。

• 批准号: 8730975
• 负责人: Christel H. Uittenbogaart
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730975
• 关键词: Address; Antibody Formation; Antigens; B-Cell Activation; B-Lymphocytes; BCL6 gene; BLR1 gene; CD3 Antigens; CD4 Positive T Lymphocytes; Cell physiology; Cells; Data; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Immune System Diseases; Immune response; Individual; Infection; Lead; Lymphoid Follicle; Lymphoid Tissue; Maintenance; Methods; Mus; Names; Pathogenesis; Phenotype; Play; Population; Reagent; Regulatory T-Lymphocyte; Research; Role; SIV; Spleen; Structure of germinal center of lymph node; T-Lymphocyte; Thymus Gland; Tonsil; Viral; defined contribution; novel; novel strategies; novel therapeutic intervention; public health relevance; viral DNA

DESCRIPTION (provided by applicant): Identification of cells that harbor viral DNA and contribute to the HIV reservoir is a critical milestone in the search for a functional cure of HIV infected individuals. HIV replication occurs mainly in lymphoid tissues and T follicular helper cells have been identified as a major CD4+ T cell population where HIV and SIV replication take place. In addition to serving as a viral reservoir, infection of T follicular helper cells, which ae essential for germinal center (GC) formation and for antibody (Ab) production by B cells, can lead to the dysregulation of humoral immune responses, including aberrant T and B cell function, resulting in hyper-gammaglobulinemia, polyclonal activation and a decrease in antigen specific Ab production. Regulatory T cells play an important role in keeping immune responses in check. Recently, regulatory T cells that are located in GC in the murine spleen have been described and named T Follicular Regulatory cells (TFR). These cells have been found to express FoxP3, CD4, CXCR5 and Bcl6 and to develop from natural regulatory T cells in the murine thymus. Preliminary data show that cells with the phenotype of TFR (CD3+, FOXP3+, CXCR5+, BCL6+) are present in the human tonsil which leads to our hypothesis that TFR play a role in HIV pathogenesis and the maintenance of the HIV reservoir observed in T follicular helper cells. We propose to use our established methods as well as novel approaches and unique reagents to address this hypothesis with the following specific aims: 1) To determine whether T Follicular Regulatory cells (TFR) harbor HIV and to define their contribution to the HIV reservoir. 2) To determine whether TFR are functionally impaired by HIV infection, and if this contributes to the HIV-associated immune dysfunction. The present proposal represents a unique collaborative approach to elucidate cells contributing to the HIV reservoir in the lymphoid tissues, which is a major obstacle in finding a cure for HIV infected individuals. The results of the proposed research, to characterize how TFR impact B cell function in HIV infection and their role in maintaining the reservoir in lymphoid tissues, will contribute to new therapeutic approaches for a functional cure of HIV infected individuals.

描述（由申请人提供）：鉴定携带病毒 DNA 并有助于 HIV 储存的细胞是寻找 HIV 感染者功能性治愈方法的一个重要里程碑。 HIV复制主要发生在淋巴组织中，并且滤泡辅助T细胞已被确定为主要的CD4+T细胞群，HIV和SIV复制在这里发生。除了充当病毒储存库之外，滤泡辅助 T 细胞（对于生发中心 (GC) 形成和 B 细胞产生抗体 (Ab) 至关重要）的感染还可导致体液免疫反应失调，包括异常 T和 B 细胞功能，导致高丙种球蛋白血症、多克隆激活和抗原特异性抗体产生减少。调节性 T 细胞在控制免疫反应方面发挥着重要作用。最近，位于小鼠脾脏GC中的调节性T细胞被描述并命名为滤泡调节性T细胞（TFR）。这些细胞被发现表达 FoxP3、CD4、CXCR5 和 Bcl6，并由小鼠胸腺中的天然调节性 T 细胞发育而来。初步数据显示，人类扁桃体中存在具有 TFR 表型的细胞（CD3+、FOXP3+、CXCR5+、BCL6+），这导致我们假设 TFR 在 HIV 发病机制和 T 滤泡辅助细胞中观察到的 HIV 储存库的维持中发挥作用。细胞。我们建议使用我们已建立的方法以及新颖的方法和独特的试剂来解决这一假设，其具体目标如下：1）确定滤泡调节T细胞（TFR）是否携带HIV并确定它们对HIV储存库的贡献。 2) 确定 TFR 是否因 HIV 感染而功能受损，以及这是否会导致 HIV 相关的免疫功能障碍。本提案代表了一种独特的合作方法，用于阐明淋巴组织中艾滋病毒储存库的细胞，这是寻找艾滋病毒感染者治愈方法的主要障碍。拟议研究的结果旨在描述 TFR 如何影响 HIV 感染中的 B 细胞功能及其在维持淋巴组织储存库中的作用，这将有助于为 HIV 感染者的功能性治愈提供新的治疗方法。