Enhancing DNA vaccine potency by modifying the properties of antigen-presenting cells

Abstract

DNA vaccines represent a potentially promising approach for antigen-specific immunotherapy. Advances in our knowledge of the adaptive immune system have indicated that professional antigen-presenting cells, especially dendritic cells (DCs), play a key role in the generation of antigen-specific immune responses. Thus, the modification of the properties of DCs represents an important strategy for enhancing the potency of DNA vaccines. This review discusses strategies to increase the number of antigen-expressing DCs, enhance antigen expression, processing and presentation in DCs, promote the activation and function of DCs, and improve DC and T-cell interaction, in order to optimize DNA vaccine-elicited immune responses. Continuing progress in our understanding of DC and T-cell biology serves as a foundation for further improvement of DNA vaccine potency, which may lead to future clinical applications of DNA vaccines for the control of infectious diseases and malignancies.

Figure 1

Antigen presentation pathways in DCs. In the MHC class I presentation pathway, cytosolic antigens are targeted for proteasomal degradation. The resulting antigenic peptides associate with MHC class I molecules in the ER and are transported to the cell surface. In the MHC class II pathway, exogenous antigens are endocytosed and the vesicle containing antigen is fused with lysosomes, facilitating antigen degradation. The resulting vesicle is then fused with a vesicle containing MHC class II molecules, and the MHC class II molecule/antigenic peptide complexes are transported to the surface of the cell. In the context of DNA vaccines, linkage of antigen to hsp, CRT, or ETA(dII) targets antigen for proteasomal degradation and/or entry into the ER, enhancing class I presentation of antigen. Linkage of antigen to LAMP-1, Ii, or TfR targets antigen to endosomal/lysosomal compartments for improved class II antigen presentation. DC, dendritic cell; MHC, major histocompatibility complex; ER, endoplasmic reticulum; hsp, heat shock proteins; CRT, calreticulin; ETA(dII), translocation domain of Pseudomonas aeruginosa exotoxin A; LAMP-1, lysosomal-associated membrane protein type 1; Ii, MHC class II-associated invariant chain; TfR, transferrin receptor.

Figure 2

Employment of Ii for stable presentation of a desired antigenic peptide by DCs. The translated Ii-antigen peptide enters the ER and binds to an MHC class II molecule, with the antigenic peptide occupying the peptide-binding groove of the MHC molecule. In the lysosomal compartments, the Ii chain is degraded, leaving the desired antigenic peptide in the peptide-binding groove of the MHC class II molecule and allowing for the stable presentation of the antigenic peptide on the cell surface.

Figure 3

(a) Illustration of a SCT (comprising antigenic peptide, β2-microglobulin, and MHC class I heavy chain) on the cell surface. (b) The SCT gene construct.