Division of Infectious Diseases, New York University School of Medicine, New York, New York 10016, USA.
J Clin Invest. 2011 Mar;121(3):1088-101. doi: 10.1172/JCI44960. Epub 2011 Feb 21.
Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIV-activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.
浆细胞样树突状细胞 (pDCs) 是先天免疫细胞，专门用于产生 IFN-α 和激活适应性免疫反应。尽管 IFN-α 在体外抑制 HIV-1 复制，但 HIV 激活的 pDCs 在体内产生 IFN-α可能对 HIV 发病机制的贡献大于保护。我们现在已经表明，HIV 刺激的人 pDCs 在反复刺激时允许持续产生 IFN-α，表达低水平的成熟分子，并刺激弱的 T 细胞反应。HIV 刺激的 pDCs 持续产生 IFN-α与 IRF7 水平升高相关，并且依赖于自分泌 IFN-α/β 受体反馈环。因为已经表明 TLR9 激动剂的早期内体运输导致 IFN-α 途径的强烈激活和 NF-κB 途径的弱激活，我们试图研究 HIV（TLR7 激动剂）的早期内体运输是否导致我们观察到的 IFN-α 产生表型。我们证明 HIV 优先在人 pDCs 中运输到早期内体，因此使 pDCs 偏向部分成熟、持续分泌 IFN-α 的表型。
