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: 8927527
• 负责人: Christel H. Uittenbogaart
• 金额: $ 19.25万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927527
• 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; Health; 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; 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储库的细胞是寻求HIV感染者功能性治愈的关键里程碑。HIV复制主要发生在淋巴组织中，并且T滤泡辅助细胞已被鉴定为HIV和SIV复制发生的主要CD4+ T细胞群体。除了充当病毒库之外，T滤泡辅助细胞（其对于生发中心（GC）形成和B细胞产生抗体（Ab）是必需的）的感染可导致体液免疫应答的失调，包括异常的T和B细胞功能，导致高丙种球蛋白血症、多克隆活化和抗原特异性Ab产生的减少。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细胞已被描述并命名为T滤泡调节细胞（TFR）。已发现这些细胞表达FoxP3、CD 4、CXCR 5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，具有TFR（CD3+，FOXP3+，CXCR5+，BCL 6+）表型的细胞存在于人扁桃体中，这导致我们的假设，即TFR在HIV发病机制和在T滤泡辅助细胞中观察到的HIV储库的维持中起作用。我们建议使用我们建立的方法以及新的方法和独特的试剂来解决这一假设，具体目标如下：1）确定T滤泡调节细胞（TFR）是否携带HIV并确定它们对HIV库的贡献。2)确定TFR是否因HIV感染而功能受损，以及这是否有助于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，以阐明淋巴组织中有助于HIV储库的细胞，这是找到治愈HIV感染者的主要障碍。拟议研究的结果，以表征TFR如何影响HIV感染中的B细胞功能及其在维持淋巴组织中的储库中的作用，将有助于HIV感染个体的功能性治愈的新治疗方法。