ABSTRACT
Three different types of CpG oligodeoxynucleotides (CpG ODNs) induced striking different immune responses via the activation of a TLR9-dependent pathway. CpG ODNs that selectively induce production of IFNα (Type D and A ODNs) are characterized by a predominantly phosphorodiester backbone, a CpG motif flanked by self-complementary bases, and a poly-guanosine (poly-G) tail on the 3′ end (or 3′ and 5′ for A ODN) that facilitates G tetrad formation and ODN multimerization. Binding and uptake of poly-G bearing ODNs are facilitated by cell membrane scavenger receptors such as CXCL16 that bind the poly-G strand. Inside cells, these ODNs are retained in early or recycling endosomes where they interact with TLR9 and signal via MyD88 and IRF7 to induce plasmacytoid dendritic cells (pDCs) to secrete high levels of IFNα. Unlike other types of CpG ODNs (K/B or C), ODN types D and A do not stimulate pDC maturation or induce polyclonal B cell activation directly.
