Suppressive Oligodeoxynucleotides Promote the Development of Th17 Cells

Christian Bode,Xiang-Ping Yang,Dennis M Klinman,Hiu Kiu,Markus M Heimesaat

doi:10.1371/journal.pone.0067991

Abstract

Synthetic oligonucleotides containing repetitive TTAGGG motifs mimic the immunosuppressive activity of telomeric DNA. These suppressive oligonucleotides (Sup ODN) are effective in the treatment/prevention of various inflammatory and autoimmune diseases in mice. The therapeutic activity of Sup ODN was originally attributed to the inhibition of Th1 cell activation. Current results indicate that Sup ODN also promote the maturation of naive CD4+ T cells into Th17 effectors. The generation of Th17 cells is linked to the prolonged activation of signal transducer and activator of transcription (STAT)3 mediated by suppressor of cytokine signaling 3 (SOCS3) inhibition. In vivo studies show that treatment with Sup ODN promotes Th17 responsiveness under physiological conditions, increasing host resistance to Candida albicans infection. These findings support the development of Sup ODN to suppress pathological inflammatory conditions and improve host resistance to fungal pathogens.

Highlights

DNA has multiple and complex effects on the immune system
Synthetic oligonucleotides (ODN) containing repetitive TTAGGG motifs mimic the ability of telomeric DNA to prevent and treat a variety of inflammatory and autoimmune diseases [2,3,4,5,6,7] This suppressive activity was initially attributed to the ability of Sup ODN to inhibit the differentiation of naive CD4+ T cells into Th1 effectors by blocking the phosphorylation of STAT1 and STAT4, thereby reducing the production of IFNc which is critical for the maintenance of the Th1 response [5,8,9]
The inclusion of Sup ODN increased the number of Th17 cells generated from highly purified naive CD4+ T cells by

Summary

Introduction

DNA has multiple and complex effects on the immune system. For example, the repetitive TTAGGG motifs present in the telomeric ends of mammalian chromosomes have immunosuppressive properties [1]. Synthetic oligonucleotides (ODN) containing repetitive TTAGGG motifs mimic the ability of telomeric DNA to prevent and treat a variety of inflammatory and autoimmune diseases [2,3,4,5,6,7] This suppressive activity was initially attributed to the ability of Sup ODN to inhibit the differentiation of naive CD4+ T cells into Th1 effectors by blocking the phosphorylation of STAT1 and STAT4, thereby reducing the production of IFNc which is critical for the maintenance of the Th1 response [5,8,9] These changes indirectly supported the generation of Th2-dominated immune responses. Th17 cells play a critical role in defending the host from extracellular pathogens, as widely demonstrated by studies involving infection with Candida albicans [17]

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Conclusion