Modulating anti-HIV immunity by plasmacytoid dendritic cells

描述（由申请人提供）：人浆细胞样树突状细胞（pDC）是血液树突状细胞（DC）的一个罕见亚群，不同于髓系CD11c+，“常规”DC （cDC）。通过在病毒感染反应中产生高水平的I型IFN， pDC在先天和适应性抗病毒免疫反应之间起关键作用。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。CD4介导的HIV-1内吞作用和随后的基因组RNA激活TLR7后，pDCs而非cdc会被激活。活化的pDCs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。与诱导这些抗病毒反应相反，hiv激活的pDCs同时以TLR7依赖的方式诱导调节性细胞（treg）从初始静息CD4+ T细胞分化。Treg的生成需要吲哚胺2,3-双加氧酶（IDO）的表达，IDO是一种将色氨酸分解为犬尿氨酸的酶，在添加特异性抑制剂1甲基色氨酸后，它被逆转。产生的T regs（“诱导T regs”）抑制活化T细胞的增殖和cDC的成熟，从而减弱正在进行的适应性免疫反应的诱导。因此，pDCs抑制病毒复制，促进抗病毒免疫，但同时也限制了免疫激活的程度。这种新发现的pDCs特性与HIV感染尤其相关，在HIV感染中，控制过度的免疫激活对于防止病毒传播和疾病进展至关重要。在此应用中，我们建议：(1)确定hiv依赖性，pdc诱导的T regg分化的机制，特别是IDO；(2)确定Tregs抑制T细胞生长和cDC激活的调控过程；(3)建立pdc介导的Treg在hiv感染者体内诱导的相关性。这些研究将极大地提高我们对pDC被HIV激活后的事件的理解，并可能导致临床应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. PUBLIC HEALTH RELEVANCE: These studies will investigate the mechanisms used by the HIV virus to evade the immune system. Specifically, we will explore how HIV induces the generation of T cells which have suppressive qualities and block the development of several beneficial anti-viral responses. By understanding how these suppressive T cells are generated we can devise strategies to modulate their function and promote anti-viral immunity.