Article: The DNA Sugar Backbone 2' Deoxyribose Determines Toll-like Receptor 9 Activation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2008-03, Vol.28 (3), p.315-323
• Main Authors: Haas, Tobias, Metzger, Jochen, Schmitz, Frank, Heit, Antje, Muller, Thomas, Latz, Eicke, Wagner, Hermann
• Format: Article
• Language: English
• ISSN: 1074-7613
• DOI: 10.1016/j.immuni.2008.01.013

CpG motifs within phosphorothioate (PS)-modified DNA drive Toll-like receptor 9 (TLR9) activation, but the rules governing recognition of natural phosphodiester (PD) DNA are less understood. Here, we showed that the sugar backbone determined DNA recognition by TLR9. Homopolymeric, base-free PD 2' deoxyribose acted as a basal TLR9 agonist as it bound to and activated TLR9. This effect was enhanced by DNA bases, even short of CpG motifs. In contrast, PS-modified 2' deoxyribose homopolymers acted as TLR9 and TLR7 antagonists. They displayed high affinity to both TLRs and did not activate on their own, but they competitively inhibited ligand-TLR interaction and activation. Although addition of random DNA bases to the PS 2' deoxyribose backbone did not alter these effects, CpG motifs transformed TLR9-inhibitory to robust TLR9-stimulatory activity. Our results identified the PD 2' deoxyribose backbone as an important determinant of TLR9 activation by natural DNA, restrict CpG-motif dependency of TLR9 activation to synthetic PS-modified ligands, and define PS-modified 2' deoxyribose as a prime effector of TLR9 and TLR7 inhibition.