T follicular regulatory cells, a potential HIV reservoir.

描述（由申请人提供）：鉴定携带病毒DNA并有助于HIV储存库的细胞是寻找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，T滤泡辅助细胞已被确定为发生HIV和SIV复制的主要CD4+ T细胞群。T滤泡辅助细胞是生发中心（GC）形成和B细胞产生抗体（Ab）所必需的，除了作为病毒储存库外，T滤泡辅助细胞的感染可导致体液免疫反应失调，包括T和B细胞功能异常，导致高γ球蛋白血症、多克隆活化和抗原特异性Ab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，研究人员描述了位于小鼠脾脏GC中的调节性T细胞，并将其命名为T滤泡调节性T细胞（T Follicular regulatory cells， TFR）。这些细胞已被发现表达FoxP3、CD4、CXCR5和Bcl6，并从小鼠胸腺的自然调节性T细胞发育而来。初步数据显示，具有TFR表型的细胞（CD3+, FOXP3+, CXCR5+, BCL6+）存在于人类扁桃体中，这导致了我们的假设，即TFR在HIV发病和T滤泡辅助细胞中观察到的HIV库的维持中发挥作用。我们建议使用我们现有的方法以及新方法和独特的试剂来解决这一假设，具体目的如下：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，以及这是否与HIV相关的免疫功能障碍有关。目前的建议代表了一种独特的合作方法，以阐明淋巴组织中有助于艾滋病毒库的细胞，这是寻找治愈艾滋病毒感染者的主要障碍。研究结果表明，TFR在HIV感染中如何影响B细胞功能，以及它们在维持淋巴组织储库中的作用，将有助于为HIV感染者的功能性治愈提供新的治疗方法。

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.