Authors: Haas, Tobias; Schmitz, Frank; Heit, Antje; Wagner, Hermann

Source: Immunology, Volume 126, Number 2, February 2009 , pp. 290-298(9)

Publisher: Wiley-Blackwell

Abstract:

Summary

Single-stranded versus multimeric phosphorothioate-modified CpG oligodeoxynucleotides (ODNs) undergo differential endosomal trafficking upon uptake into plasmacytoid dendritic cells (pDCs), correlating with Toll-like receptor-9-dependent pDC maturation/activation (single-stranded B-type CpG ODN) or interferon-α (IFN-α) induction (multimeric A-type CpG ODN), respectively. As was recently shown, IFN-α production, other than by CpG ODNs, can also be induced in a sequence-independent manner by phosphodiester (PD) ODNs multimerized by 3′ poly-guanosine (poly-G) tails. We investigate here the type of endosomal trafficking responsible for IFN-α induction by natural PD ODN ligands. We show that 3′ extension with poly-G tails leads to multimerization of single-stranded PD ODNs and to enhanced cellular uptake into pDCs. While monomeric PD ODNs, which induce CpG-dependent Toll-like receptor-9 stimulation and pDC maturation/activation, localized to late endosomal/lysosomal compartments, the poly-G multimerized PD ODNs, which induce CpG-independent IFN-α production, located to vesicles with a distinct, `early' endosomal phenotype. We conclude that poly-G-mediated multimerization of natural PD ODNs allows for sequence-independent, Toll-like receptor-9-dependent IFN-α induction in pDCs by combining three distinct effects: relative protection of sensitive PD ODNs from extracellular and intracellular DNase degradation, enhanced cellular uptake and preferential early endosomal compartmentation.

Keywords: interferon-α production; plasmacytoid dendritic cells; phosphodiester DNA; sequence independence; Toll-like receptor-9

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2567.2008.02897.x

Publication date: 2009-02-01

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