Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist

Area of Science:

• Immunology
• Nanotechnology
• Vaccinology

Background:

• CpG DNA is a promising immunotherapeutic agent targeting Toll-like receptor 9 (TLR9).
• Existing CpG oligodeoxynucleotides (ODNs) struggle to activate both B cells and plasmacytoid dendritic cells effectively in a stable nanoparticle form.
• Developing "all-in-one" CpG ODNs remains a challenge.

Purpose of the Study:

• To generate a novel nanoparticulate CpG ODN (K3-SPG) by wrapping K CpG ODN (K3) with schizophyllan (SPG).
• To evaluate the immune-stimulating capacity of K3-SPG, focusing on its ability to induce type I and type II Interferon (IFN) and its adjuvant potential.

Main Methods:

• Generation of K3-SPG by complexing K CpG ODN (K3) with schizophyllan (SPG).
• Stimulation of human peripheral blood mononuclear cells (PBMCs) with K3-SPG.
• Assessment of IFN production and immune response induction in vitro and in vivo (murine and nonhuman primate models).

Main Results:

• K3-SPG significantly increased production of type I and type II IFN from human PBMCs, unlike K3 alone.
• K3-SPG demonstrated potent adjuvant activity for humoral and cellular immune responses, including CTL induction, to coadministered protein antigens.
• The nanoparticle formation, not Dectin-1 targeting by SPG, was key to its adjuvant activity by accumulating immune cells in lymph nodes.
• K3-SPG showed efficacy as an influenza vaccine adjuvant in vivo.

Conclusions:

• K3-SPG is a novel, stable nanoparticle capable of potent immune activation.
• This CpG ODN formulation effectively induces both humoral and cellular immunity, particularly CTLs.
• K3-SPG holds potential for immunotherapeutic applications requiring type I/II IFN and CTL induction, including vaccine development.