Inhibitory oligodeoxynucleotides downregulate herpes simplex virus-induced plasmacytoid dendritic cell type I...

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Plasmacytoid dendritic cells (PDC) express Toll-like receptor 9 (TLR9), crucial for recognizing microbial nucleic acids and initiating immune responses, including type I interferon production.
• Unmethylated CpG motifs in microbial DNA activate TLR9, while inhibitory oligodeoxynucleotides (iODN) can suppress this signaling pathway.
• TLR9 activation by PDC is vital for defense against viral infections and orchestrates innate and adaptive immunity.

Purpose of the Study:

• To investigate the effects of TTAGGG motif-containing iODN on TLR9 signaling and PDC function.
• To determine whether iODN exclusively inhibit TLR9-mediated responses or also influence PDC maturation and T-cell activation.
• To elucidate the multifaceted roles of iODN in immune modulation for potential immunotherapeutic applications.

Main Methods:

• Stimulation of human PDC with herpes simplex virus (HSV) and various oligodeoxynucleotides (ODN), including iODN.
• Analysis of type I interferon production, PDC maturation markers (costimulatory molecules, MHC), and T-cell stimulatory capacity.
• Coculture experiments with autologous T cells to assess iODN-induced changes in T regulatory cell generation and T-cell cytokine production (IFN-gamma).

Main Results:

• TTAGGG motif-containing iODN effectively blocked HSV-induced type I interferon production by PDC via TLR9 inhibition.
• Despite blocking interferon production, iODN (and control ODN) promoted PDC maturation and upregulated key surface molecules.
• iODN-treated PDC exhibited enhanced T-cell stimulatory functions, inducing more T regulatory cells and increasing T-cell IFN-gamma production upon HSV stimulation.

Conclusions:

• iODN possess dual functions: they inhibit TLR9-dependent type I interferon production but also act as activators of PDC maturation and T-cell priming.
• These findings highlight that iODN can modify PDC activation and T-cell responses beyond simple TLR9 pathway inhibition.
• Understanding these complex effects is critical for developing immunotherapeutic strategies using iODN to modulate immune responses, as they may not only suppress but also activate immune cells.