Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8(+) T cell response:...

Here we demonstrated the importance of targeting antigens (Ags) to dendritic cell (DC) receptors to achieve an efficient cytotoxic T cell response which was associated with a strong activation of DC. Pegylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used to encapsulate ovalbumin (OVA) as a model Ag. This PLGA complex, together with Toll like receptor (TLR) 3 and 7 ligands, was then targeted to distinct DC cell-surface molecules. These cell-surface molecules, including CD40, a TNF-α family receptor, DEC-205, a C-type lectin receptor and CD11c, an integrin receptor, were targeted by means of specific monoclonal antibodies (mAbs) coupled to the NP. The efficiency of these different targeting strategies to activate DC and elicit a potent CD8(+) T cell response was studied. PLGA-(Ag/TLR3+7L) NP was more efficiently targeted to and internalized by DC in vitro compared to the control non-targeted NP. We observed a small but significantly improved internalization of CD40-targeted NP compared to DEC-205 or CD11c targeted NP. In contrast to non-targeted NP, all targeted NPs equally stimulated IL-12 production and expression of co-stimulatory molecules by DC, inducing strong proliferation and IFN-y production by T cells in vitro. Moreover, subcutaneous vaccination with CD40, DEC-205 and CD11c-targeted NP consistently showed higher efficacy than non-targeted NP in stimulating CD8+ T cell responses. However, all targeted NP vaccines showed an equal capacity to prime cytotoxic CD8+ T cells, which subsequently were able to induce targeted cell lysis. In conclusion, delivery of NP-vaccines to DC by targeting via cell-surface molecules leads to strong enhancement of vaccine potency and induction of T cell responses compared to non-specific delivery of NP to DC.