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

描述（由申请人提供）：尽管干扰素-1 （IFN- 1）是一种以其抗病毒作用而闻名的细胞因子，但在低生理浓度下，它可能对适应性和先天免疫系统的正常功能也很重要，而在高浓度下，它具有免疫抑制作用。在这方面，IFN-?？与HIV-1感染的控制无关，可能是免疫激活导致HIV-1发病的标志。我们的初步数据显示，hiv -1诱导的IFN-?？通过破坏IL-7/IL7R通路，生产抑制早期人类T细胞发育。此外，我们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）组成性地表达IFN-？和低水平的次级反应蛋白MxA。相比之下，外周血淋巴器官（来自同一供体）的淋巴细胞和pDC不组成性地表达IFN-。这些结果支持了胸腺中低水平IFN-?？对T细胞发育的正常功能很重要然而，高水平的IFN-?？延长hiv -1诱导的IFN-?？可能会干扰正常T细胞的发育，从而干扰外周T细胞的重建。因此，尽管IFN-?？可以抑制HIV-1在体外的复制，而IFN-?？该疗法在体内显示出好坏参半的结果，很可能其免疫抑制作用超过其抗病毒活性，从而促进了HIV-1的发病机制。根据我们的初步数据，我们的中心假设是高水平的IFN-?？在HIV-1感染期间伴随免疫激活，损害T细胞（再）生成，并且pDC在这一过程中起重要作用。我们将使用我们现有的方法，以及新的方法和独特的试剂来检验我们的假设。实验将用hiv诱导的IFN-?？在人源化小鼠模型和体外T细胞发育实验中，提出了以下具体目标：研究HIV-1诱导IFN-?？抑制t细胞的发育和重建。2. 目的探讨浆细胞样树突状细胞（pDC）在胸腺中的作用。3. 为了研究IFN-?？诱导的MxA或其他次级应答蛋白抑制嗜CCR5-和嗜cxcr4的HIV-1的复制。目前的建议代表了一种独特的合作方法来阐明IFN-?？和pDC在HIV-1感染中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-?？（IFN-??）是一种以其抗病毒作用而闻名的细胞因子，在低生理性浓度下，它可能对适应性和先天免疫系统的正常功能也很重要，而在高浓度下，它具有免疫抑制作用。在这方面，IFN-?？与HIV-1感染的控制无关，可能是免疫激活导致HIV-1发病的标志。目前的建议代表了一种独特的合作方法来阐明IFN-?？和pDC在HIV-1感染中T细胞发育和重建中的作用。深入了解IFN-??的分子机制诱导T细胞发育阻滞将促进免疫调节治疗干预措施的发展，以抵消受损的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.