Immunobiology of Regulatory T Cells in HIV Infection

描述（由申请人提供）：现在有令人信服的证据表明，调节性T细胞（Tregs）抑制免疫激活，并在HIV感染期间受到干扰。利用Treg功能的机制与控制HIV感染期间的慢性免疫激活或相反地促进HIV特异性免疫反应有关。然而，在我们对Treg细胞生物学的理解中，特别是在HIV发病机制方面，仍然存在一些关键问题和空白。由于缺乏特异性标记物，HIV患者的Tregs分析很复杂。目前尚不清楚Treg细胞损失是否会导致HIV感染期间的炎症，或者它们是否会通过抑制HIV特异性免疫反应而有害。在之前的资助期间，我们在了解Treg细胞分化方面取得了重大进展，并建立了在体外扩增Treg细胞的方法。我们发现了一种叫做GARP的细胞表面分子，它在真实激活的Tregs上高度特异性地表达。我们还发现促炎细胞因子IL-1和TNF的受体及其各自的诱饵在人Treg细胞上优先表达。此外，我们开发了一种新的技术来扩展和基因工程treg与hiv特异性T细胞受体（TCR），以确定TCR信号在其抑制功能中的作用。在本提案中，我们的目标是利用这些创新工具和技术进步：(1)在一项前瞻性研究中确定Tregs与接受或未接受治疗的hiv感染者免疫激活状态的关联；(2)确定Tregs在感知和抑制炎症中的功能，以及这种功能在HIV感染期间是否受到损害；(3)确定Tregs在操纵hiv特异性免疫应答中的特异性和抑制作用；(4)建立实验框架，解码肽亲和力和浓度在通过TCR信号调节Treg反应中的作用。总之，这些新方法将对在HIV感染期间使用真正的Tregs作为生物标志物，确定它们在HIV感染期间免疫激活和抑制HIV特异性免疫反应中的作用具有广泛的意义。这一知识也可用于设计更有效的艾滋病毒疫苗。

DESCRIPTION (provided by applicant): There is now compelling evidence that regulatory T cells (Tregs) suppress immune activation and are perturbed during HIV infection. Exploiting the mechanisms of Treg function is relevant for controlling chronic immune activation during HIV infection or conversely in boosting HIV-specific immune responses. However, several key questions and gaps remain in our understanding of Treg cell biology, especially in the context of HIV pathogenesis. The analysis of Tregs in HIV patients is complicated due to lack of specific markers. It is also still not clear whether Treg cell loss contributes to inflammation during HIV infection or whether they are detrimental by suppressing HIV-specific immune responses. During the previous grant period we made major advances in understanding Treg cell differentiation and established methods to expand them in vitro. We discovered a cell surface molecule, called GARP, highly specifically expressed on bona fide activated Tregs. We also found that receptors for proinflammatory cytokines IL-1 and TNF and their respective decoys are preferentially expressed on human Treg cells. Additionally, we developed a novel technology to expand and genetically engineer Tregs with HIV-specific T cell receptors (TCRs) to determine the role of TCR signals in their suppressive function. In this proposal we aim to use these innovative tools and technical advances to: (1) Determine association of Tregs with immune activation status of HIV-infected individuals either with or without treatment in a prospective study; (2) Determine the function of Tregs in sensing and suppressing inflammation and whether this function is compromised during HIV infection; (3) Determine the specificity and suppressive role of Tregs in manipulating HIV-specific immune responses; and (4) Develop an experimental framework to decode the role of peptide affinity and concentrations in regulating Treg responses through TCR signaling. Together, these new approaches will have wide range of implications for using bona fide Tregs as biomarkers during HIV infection, defining their role in immune activation and in suppressing HIV-specific immune responses during HIV infection. This knowledge can also be exploited to design more potent HIV vaccines.