Modulating anti-HIV immunity by plasmacytoid dendritic cells

通过浆细胞样树突状细胞调节抗 HIV 免疫

基本信息

批准号：
8607497
负责人：
Melissa Victoria Fernandez
金额：
$ 2.31万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2014-06-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607497
关键词：
Antiviral Agents Antiviral Response Attenuated Blocking Antibodies Blood CD4 Positive T Lymphocytes Cell Maturation Cells Data Dendritic Cells Dendritic cell activation Development Dioxygenases Disease Progression Endocytosis Enzymes Event Generations Genomics HIV HIV Infections HIV-1 Human IL2RA gene ITGAX gene Immune Immune response Immune system Immunity Infection Infection Control Inflammatory Interferon Type I Intervention Kynurenine Laboratories Ligation Link Lymphoid Tissue Mediating Mediator of activation protein Modeling Molecular Monitor Mus Mutate Myelogenous NF-kappa B Pathway interactions Phosphorylation Phosphorylation Site Play Process Production Property RNA Regulation Regulatory T-Lymphocyte Rest Role Signal Transduction Site Small Interfering RNA T-Lymphocyte TLR7 gene Testing Time Tryptophan Tryptophan 2,3 Dioxygenase Up-Regulation Viral Viral Antigens Virus Virus Diseases Work adaptive immunity chemokine cytokine immune activation improved in vivo indolamine inhibitor/antagonist knock-down member methyl tryptophan pathogen prevent research study response viral RNA

项目摘要

ABSTRACT 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 na¿ve 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) Determine the role of TLR7 and TLR9 in HIV-induced activation of IDO; (2) Elucidate the players in the noncanonical NFkB pathway for IDO expression; (3) .Examine the pDC-derived products that cause T reg generation. 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.

抽象的人浆细胞类动物树突状细胞（PDC）构成了罕见的血液树突状细胞（DC），与髓样CD11C+，常规的DC（CDC）不同。通过响应病毒感染的高水平I型IFN的产生，PDC是先天性和适应性抗病毒免疫调查的关键联系。我实验室的最新观察结果强调了它们在HIV-1感染免疫调节中的特殊作用。 CD4介导的HIV-1内吞作用以及随后用基因组RNA激活TLR7后，PDC（而不是CDC）进行活化。活化的PDC上调了共刺激分子，产生促炎性细胞因子和趋化因子，并以旁观者的方式激活未成熟的CDC。作为对这些抗病毒反应的诱导的对立，HIV激活的PDC只是以TLR7的方式诱导了从NA¿VE静止的CD4+ T细胞中的Tregulation细胞（Treg）分化。 Treg的产生需要吲哚胺2,3-二氧酶（IDO）的表达，这是一种将色氨酸分解为Kynurenine的酶，因为在添加了特定的抑制剂1甲基甲基化合物后，它会反转。产生的T条例（可诱导的T条例）抑制了活化的T细胞的增殖和CDC的成熟，从而减弱了持续的适应性免疫调查的诱导。 PDC抑制病毒复制并促进抗病毒免疫学，但同时限制了免疫学激活程度。 PDCS的新归因性质在HIV感染中尤其重要，在HIV感染中，控制过多的免疫学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TLR7和TLR9在HIV诱导的IDO激活中的作用；（2）阐明了以IDO表达的非规范NFKB途径中的玩家；（3）。审查导致T Reg生成的PDC衍生产品。这些研究将大大提高我们对艾滋病毒PDC激活遵循PDC激活的事件的理解，并可能导致临床适用的方法，以增强体内的抗HIV免疫调查。