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）的一种罕见亚群，与髓样CD 11 c+、“常规”DC（cDC）不同。通过响应病毒感染产生高水平的I型IFN，pDC充当先天性和适应性抗病毒免疫应答之间的关键环节。我的实验室最近的观察突出了它们在HIV-1感染的免疫调节中的特殊作用。pDC，而不是cDC，在CD 4介导的HIV-1内吞作用和随后用基因组RNA激活TLR 7后经历活化。活化的pDC上调共刺激分子，产生促炎细胞因子和趋化因子，并以旁观者方式活化未成熟的cDC。作为诱导这些抗病毒应答的对应物，HIV活化的pDC以TLR 7依赖性方式同时诱导T调节细胞（Tregulatory cell，Tregulatory cell）从初始静息CD 4 + T细胞分化。Treg的产生需要吲哚胺2，3-双加氧酶（IDO）的表达，IDO是一种将色氨酸分解代谢为犬尿氨酸的酶，因为它在添加特异性抑制剂1甲基-色氨酸后被逆转。产生的T细胞（“诱导型T细胞”）抑制活化T细胞的增殖和cDC的成熟，从而减弱持续的适应性免疫应答的诱导。因此，pDC抑制病毒复制并促进抗病毒免疫，但同时限制免疫活化的程度。pDC的这种新赋予的性质在HIV感染中特别相关，其中控制过度的免疫激活对于防止病毒传播和疾病进展可能是必要的。在本申请中，我们提出：（1）鉴定HIV依赖性的、pDC诱导的T reg分化的潜在机制，特别关注IDO;（2）确定Treg用于抑制T细胞生长和cDC活化的调节过程;（3）建立HIV感染患者中pDC介导的Treg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后的事件的理解，并可能导致临床上适用的方法来增强体内抗HIV免疫应答。 公共卫生相关性：这些研究将调查HIV病毒逃避免疫系统的机制。具体来说，我们将探讨艾滋病毒如何诱导产生T细胞，这些T细胞具有抑制性，并阻止几种有益的抗病毒反应的发展。通过了解这些抑制性T细胞是如何产生的，我们可以设计策略来调节它们的功能并促进抗病毒免疫。

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.