Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19973-8. doi: 10.1073/pnas.1014051107. Epub 2010 Nov 2.
Despite their low frequency, plasmacytoid dendritic cells (pDCs) produce most of the type I IFN that is detectable in the blood following viral infection. The endosomal Toll-like receptors (TLRs) TLR7 and TLR9 are required for pDCs, as well as other cell types, to sense viral nucleic acids, but the mechanism by which signaling through these shared receptors results in the prodigious production of type I IFN by pDCs is not understood. We designed a genetic screen to identify proteins required for the development and specialized function of pDCs. One phenovariant, which we named feeble, showed abrogation of both TLR-induced type I IFN and proinflammatory cytokine production by pDCs, while leaving TLR responses intact in other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine transporter 1 (PHT1) and has not previously been implicated in pDC function. The identification of the feeble mutation led to our subsequent observations that AP-3, as well as the BLOC-1 and BLOC-2 Hermansky-Pudlak syndrome proteins are essential for pDC signaling through TLR7 and TLR9. These proteins are not necessary for TLR7 or TLR9 signaling in conventional DCs and thus comprise a membrane trafficking pathway uniquely required for endosomal TLR signaling in pDCs.
尽管浆细胞样树突状细胞 (pDCs) 的频率较低，但它们在病毒感染后血液中可检测到的 I 型 IFN 大部分由其产生。内体 Toll 样受体 (TLR) TLR7 和 TLR9 是 pDCs 以及其他细胞类型识别病毒核酸所必需的，但这些共同受体的信号转导如何导致 pDCs 产生大量 I 型 IFN 的机制尚不清楚。我们设计了一项遗传筛选，以鉴定 pDCs 发育和特化功能所需的蛋白质。一种名为“微弱”的表型变体显示，pDCs 的 TLR 诱导的 I 型 IFN 和促炎细胞因子产生均被阻断，而其他细胞中的 TLR 反应则保持完整。“微弱”表型可归因于 Slc15a4 中的突变，该基因编码肽/组氨酸转运蛋白 1 (PHT1)，以前与 pDC 功能无关。发现微弱突变后，我们随后观察到 AP-3 以及 Hermansky-Pudlak 综合征相关的 BLOC-1 和 BLOC-2 蛋白对于 TLR7 和 TLR9 介导的 pDC 信号传导是必需的。这些蛋白对于经典 DC 中的 TLR7 或 TLR9 信号传导不是必需的，因此构成了内体 TLR 信号传导在 pDCs 中特有的膜转运途径。
