Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation

Abstract

Human plasmacytoid dendritic cells (PDCs) can produce interferon (IFN)-α and/or mature and participate in the adaptive immune response. Three classes of CpG oligonucleotide ligands for Toll-like receptor (TLR)9 can be distinguished by different sequence motifs and different abilities to stimulate IFN-α production and maturation of PDCs. We show that the nature of the PDC response is determined by the higher order structure and endosomal location of the CpG oligonucleotide. Activation of TLR9 by the multimeric CpG-A occurs in transferrin receptor (TfR)-positive endosomes and leads exclusively to IFN-α production, whereas monomeric CpG-B oligonucleotides localize to lysosome-associated membrane protein (LAMP)-1–positive endosomes and promote maturation of PDCs. However, CpG-B, when complexed into microparticles, localizes in TfR-positive endosomes and induces IFN-α from PDCs, whereas monomeric forms of CpG-A localize to LAMP-1–positive endosomes accompanied by the loss of IFN-α production and a gain in PDC maturation activity. CpG-C sequences, which induce both IFN-α and maturation of PDCs, are distributed in both type of endosomes. Encapsulation of CpG-C in liposomes stable above pH 5.75 completely abrogated the IFN-α response while increasing PDC maturation. This establishes that the primary determinant of TLR9 signaling is not valency but endosomal location and demonstrates a strict compartmentalization of the biological response to TLR9 activation in PDCs.

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

“…There is mounting evidence that both subcellular localization and endosomal pH can influence the ability of endosomal TLRs to signal. For example, the TLR9 response to exogenous CpG DNA is dependent on specific endosomal localization and acidification (Guiducci et al , 2006; Yao et al , 2009; Okuya et al , 2010; Hazeki et al , 2013; Duhamel et al , 2016). Sasai et al (2010) showed TLR9 signaling leading to activation of type I IFN but not pro‐inflammatory cytokine genes require TLR9 trafficking from endosomes to a specialized lysosome‐related organelle dependent on AP‐3.…”

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

“…It has been previously shown that type B CpG ODNs predominantly activate pDCs in a manner that results in phenotypic changes and pro-inflammatory cytokine production, as well as weak induction of type I IFN responses [53]. The functional activity of type B CpG ODNs is attributed to their localization to lysosome-associated membrane protein 1-positive endosomes, while activation of TLR9 by type A CpG ODNs occurs in transferrin receptor-positive endosomes [54].…”

Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus

“…12 The distinct biology of each class is thought to be related to their differential capacity to form secondary or higher-order structures and localize to discrete intracellular compartments. 16 The A-class have phosphodiester/phosphorothioate chimeric backbones, form complex tertiary structures, and are poor at activating B cells but potent for inducing IFN-␣ production from pDCs. B-class CpG ODNs have a whole phosphorothioate backbone, do not form secondary or tertiary structures, and are potent B cell activators but weak for inducing pDCs to produce IFN-␣.…”