Modulating anti-HIV immunity by plasmacytoid dendritic cells

描述(申请人提供)：人浆细胞样树突状细胞(PDC)是一种罕见的血液树突状细胞(DC)亚群，不同于髓系CD11c+，“传统”DC(CDC)。通过产生高水平的I型干扰素来应对病毒感染，PDC是先天和获得性抗病毒免疫反应之间的关键纽带。我的实验室最近的观察强调了它们在HIV-1感染的免疫调节中的特殊作用。在CD4介导的HIV-1内吞作用和随后的TLR7与基因组RNA的激活之后，PDCs而不是CDCs经历激活。活化的pDC上调共刺激分子，产生促炎细胞因子和趋化因子，并以旁观者的方式激活未成熟的CDC。作为诱导这些抗病毒反应的对立面，HIV激活的pDC以TLR7依赖的方式同时诱导T调节细胞(Tregs)从初始静止的CD4+T细胞分化为Tregs。Treg的产生需要表达吲哚胺2，3-双加氧酶(IDO)，这是一种将色氨酸分解为犬尿氨酸的酶，因为它在加入特定的抑制剂1甲基色氨酸后被逆转。产生的T调节器(“可诱导T调节器”)抑制激活的T细胞的增殖和CDC的成熟，从而减弱持续适应性免疫反应的诱导。因此，pDC抑制病毒复制，促进抗病毒免疫，但同时限制了免疫激活的程度。PDC的这一新特性与艾滋病毒感染特别相关，在艾滋病毒感染中，控制过度的免疫激活可能是防止病毒传播和疾病发展的关键。在这项应用中，我们建议：(1)确定HIV依赖、PDC诱导T细胞分化的机制(S)，特别是IDO；(2)确定Tregs用于抑制T细胞生长和CDC激活的调节过程；(3)建立PDC介导的TREG在HIV感染患者中诱导的体内相关性。这些研究将极大地提高我们对HIV激活PDC后发生的事件的理解，并可能导致临床上适用的方法来增强体内的抗HIV免疫反应。

DESCRIPTION (provided by applicant): Human plasmacytoid dendritic cells (pDC) constitute a rare subset of blood dendritic cells (DC), distinct from myeloid CD11c+, "conventional" DC (cDC). Through production of high levels of type I IFN in response to virus infection, pDC serve as a critical link between innate and adaptive antiviral immune responses. Recent observations from my laboratory have highlighted their particular role in the immune regulation of HIV-1 infection. pDCs, but not cDCs, undergo activation following CD4 mediated endocytosis of HIV-1 and subsequent activation of TLR7 with genomic RNA. Activated pDCs upregulate costimulatory molecules, produce pro-inflammatory cytokines and chemokines and activate immature cDCs in a bystander fashion. As a counterpoint to the induction of these anti-viral responses, HIV-activated pDCs simultaneously induce the differentiation of Tregulatory cells (Tregs) from naive resting CD4+ T cells, in a TLR7 dependent manner. Treg generation requires the expression of indolamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan to kynurenine, as it is reversed upon addition of the specific inhibitor 1 methyl-tryptophan. The T regs generated ("inducible T regs") inhibit the proliferation of activated T cells and maturation of cDC, thereby attenuating the induction of ongoing adaptive immune responses. Thus pDCs inhibit viral replication and promote anti-viral immunity, but at the same time limit the extent of immune activation. This newly ascribed property of pDCs is especially relevant in HIV infection where control of excessive immune activation could be essential to prevent virus dissemination and progression of disease. In this application we propose to: (1) Identify the mechanism(s) underlying HIV-dependent, pDC-induced T reg differentiation, focusing in particular on IDO; (2) Determine the regulatory processes used by Tregs to inhibit T cell growth and cDC activation; (3) Establish the in vivo relevance of pDC-mediated induction of Treg in HIV-infected patients. These studies will greatly improve our understanding of the events that follow pDC activation by HIV and potentially result in clinically applicable approaches to enhance anti-HIV immune responses in vivo.