Suppressive Oligodeoxynucleotides Inhibit Th1 Differentiation by Blocking IFN-γ- and IL-12-Mediated Signaling

Abstract

Repetitive TTAGGG motifs present at high frequency in mammalian telomeres can suppress Th1-mediated immune responses. Synthetic oligonucleotides (ODN) containing TTAGGG motifs mimic this activity and have proven effective in the prevention/treatment of certain Th1-dependent autoimmune diseases. This work explores the mechanism by which suppressive ODN block the induction of Th1 immunity. Findings indicate that these ODN inhibit IFN-γ-induced STAT1 phosphorylation and IL-12-induced STAT3 and STAT4 phosphorylation. As a result, T-bet expression is reduced as is the maturation of naive CD4+ cells into Th1 effectors. These changes indirectly support the generation of Th2-dominated immune responses. Suppressive ODN may thus represent a novel approach to influence the Th1:Th2 balance in vivo.

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

“…Interestingly, synthetic telomere repeat DNA was found to suppress the production of cytokines induced by CpG DNA, as well as by other TLR agonists, including lipopolysaccharides (LPSs) (58) and various polyclonal activators (21,59). Molecular targets for TTAGGGrepeat oligonucleotides have included STAT1 and STAT4 (60) and the lupus autoantigen Ku (61). Additionally, native DNA from telomerase-deficient mice had reduced capacity to inhibit inflammation compared to that of the control DNA (62), supporting the hypothesis that telomere-rich DNA is immunomodulatory.…”

Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

“…Previous reports demonstrated that suppressive ODN of the A151 class can down-regulate Th1 responses induced by a variety of immune stimuli (12)(13)(14)(15)(16)(17)(18)(19). The current results establish that these ODN dampen Th1 signaling by binding to and preventing the phosphorylation of STAT1 and STAT4, thereby reducing the production of IFN-␥, a cytokine critical to the maintenance of Th1 immunity.…”

“…The second class of suppressive ODN contains repetitive TTAGGG motifs patterned after those present in mammalian telomeres (12). Previous studies established that telomeric DNA and suppressive ODN containing TTAGGG motifs down-regulate the production of proinflammatory and Th1 cytokines (12)(13)(14)(15). Although initially identified by their ability to block CpG-induced immune activation, this class of suppressive ODN (typified by ODN A151) was subsequently shown to block multiple forms of immune stimulation (14 -19) and to be effective in the prevention/treatment of pathologic autoimmune responses (13,15,25).…”

“…Several recent reports indicate that suppressive oligonucleotides (ODN) 3 are capable of blocking the deleterious production of Th1 and proinflammatory cytokines (12)(13)(14)(15)(16)(17)(18)(19). One class of suppressive ODN is characterized by the presence of methylated CG or unmethylated GC sequences that selectively block CpG-induced immune activation (20 -24).…”

Potential of Transfected Muscle Cells to Contribute to DNA Vaccine Immunogenicity

“…Cytokine levels in culture supernatants were measured by ELISA, as previously described (23). Ninety-six-well Immulon H2B plates (Thermo LabSystems) were coated with first-stage IFN␥-specific Ab and then blocked with PBS 1% BSA.…”