Human microsatellite DNA mimicking oligodeoxynucleotides down-regulate TLR9-dependent and -independent activation of human immune cells

To develop novel immunoregulatory oligodeoxynucleotides (ODNs), we have designed a series of ODNs based on the sequences in human microsatellite (MS) DNA. The ODNs, designated as human MS DNA mimicking ODNs (MS ODNs), have been studied for their inhibitory effects on human immune cells activated by TLR9-dependent and -independent stimulations. We find for the first time that MS08, a MS ODN composed entirely of TC dinucleotide (TC) repeats, inhibits CpG ODN (TLR9 ligand)-induced human PBMCs proliferation, CD80 and CD86 expression and production of interferon. In addition, MS08 also inhibits the proliferation of human PBMCs stimulated by PHA, PMA and alloantigens in a TLR9-independent manner. The inhibition correlates with competition of binding and uptake between MS08 and CpG ODN in human PBMCs. Structurally, TC, CT or CCT are revealed as essential suppressive motifs required for the inhibition. These findings suggest that TC repeat containing MS ODN could be of therapeutic use in pathologic situations due to excessive activation of immune cells.