IFN-a and pDC in HIV infection: impact on T cell development and reconstitution

描述(申请人提供)：虽然干扰素-1(干扰素-？)是一种细胞因子，以其抗病毒作用而闻名，但在低生理浓度下对适应性免疫系统和先天免疫系统的正常运作也可能是重要的，而在高浓度时它具有免疫抑制作用。在这方面，干扰素-β水平升高。它们与HIV-1感染的控制无关，很可能是免疫激活的迹象，有助于HIV-1的发病。我们的初步数据显示，HIV-1诱导的干扰素？？生产通过损害IL-7/IL7R途径来抑制人类T细胞的早期发育。此外，我们还发现，在正常胸腺组织中，成熟胸腺细胞和浆细胞样树突状细胞(PDC)结构性地表达干扰素-β。其次级反应蛋白MxA处于低水平。相反，外周淋巴器官中的淋巴细胞和PDC(来自同一供者)并不结构性地表达干扰素-β。这些结果支持这样的观点，即在胸腺中，低水平的干扰素？对T细胞发育的正常功能很重要。然而，高水平的干扰素-？？延长HIV-1诱导的干扰素-？？可能会干扰正常的T细胞发育，从而干扰外周T细胞的重建。因此，虽然干扰素-？？在体外可以抑制HIV-1的复制，而干扰素？治疗在体内的结果好坏参半，其免疫抑制作用可能超过其抗病毒活性，从而导致HIV-1的发病。根据我们的初步数据，我们的中心假设是高水平的干扰素-？？在HIV-1感染过程中伴随着免疫激活，会损害T细胞(再)的生成，而PDC在这一过程中起着至关重要的作用。我们将使用我们已有的方法以及新的方法和独特的试剂来检验我们的假设。实验将使用HIV诱导的干扰素-？？在人源化小鼠模型和体外T细胞发育实验中，提出了以下特定目的：1.探讨HIV-1诱导干扰素？的机制。抑制T细胞的发育和重建。2.研究浆细胞样树突状细胞(PDC)在胸腺中的作用。3.探讨干扰素-β？诱导的MXA或其他次级反应蛋白抑制嗜CCR5和CXCR4的HIV-1的复制。本提案代表了一种独特的协作方法来阐明干扰素-？？的作用。和PDC在HIV-1感染的T细胞发育和重建中的作用。从拟议的实验中获得的信息将对免疫调节疗法治疗HIV-1感染患者产生影响。公共卫生相关性：尽管干扰素-？？(干扰素-？？)是一种细胞因子，以其抗病毒作用而闻名，但在低浓度时对适应性免疫系统和先天免疫系统的正常运作可能也很重要，而在高浓度时它具有免疫抑制作用。在这方面，干扰素-β水平升高。它们与HIV-1感染的控制无关，很可能是免疫激活的迹象，有助于HIV-1的发病。本提案代表了一种独特的协作方法来阐明干扰素-？？的作用。和PDC在HIV-1感染的T细胞发育和重建中的作用。深入了解干扰素的分子机制？？诱导阻断T细胞发育将促进免疫调节性治疗干预措施的发展，以对抗受损的T细胞发育和再生。

DESCRIPTION (provided by applicant): Although Interferon-1 (IFN-?) is a cytokine known for its antiviral effects, it may be also be important for normal functioning of the adaptive and innate immune system at low, physiologic concentrations, while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. Our preliminary data show that HIV-1-induced IFN-?? production inhibits early stages of human T cell development by impairing the IL-7/IL7R pathway. In addition we found that in normal thymus tissue, mature thymocytes and plasmacytoid dendritic cells (pDC) constitutively express IFN-?? and its secondary response protein MxA at low levels. In contrast, lymphocytes and pDC in peripheral lymphoid organs (from the same donor) do not constitutively express IFN-??. These results support the notion that in the thymus, low levels of IFN-?? are important for normal functioning of T cell development. However, high levels of IFN-?? and prolonged HIV-1-induced IFN-?? are likely to disturb normal T cell development and thereby peripheral T cell reconstitution. Thus, although IFN-?? can suppress HIV-1 replication in vitro, and IFN-?? therapy has shown mixed results in vivo, it is likely that its immunosuppressive effects outweigh its antiviral activity thereby contributing to HIV-1 pathogenesis. Based on our preliminary data our central hypothesis is that high levels of IFN-?? which accompany immune, activation during HIV-1 infection, impair T cell (re)generation and that pDC play an essential role in this process. We will use our established methods as well as novel approaches and unique reagents to test our hypothesis. Experiments will be performed with HIV-induced IFN-?? in humanized mouse models and in vitro T cell development assays as proposed in the following specific aims: 1. To investigate the mechanisms by which HIV-1 induced IFN-?? inhibits T-cell development and reconstitution. 2. To characterize the role of plasmacytoid dendritic cells (pDC) in the thymus. 3. To investigate the mechanisms by which IFN-?? induced MxA or other secondary response proteins suppress replication of CCR5- and CXCR4-tropic HIV-1. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Information gained from the proposed experiments will have implications for the treatment of HIV-1 infected patients with immunomodulatory therapies. PUBLIC HEALTH RELEVANCE: Although Interferon-?? (IFN-??) is a cytokine known for its antiviral effects, it may also be important for normal functioning of the adaptive and innate immune system at low, physiologic, concentrations while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Insight into the molecular mechanisms underlying the IFN-?? induced block of T cell development will enhance the development of immunomodulatory therapeutic interventions to counteract impaired T cell development and regeneration.