Bioinspired vaccines to enhance MHC class-I antigen cross-presentation

Abstract

Cross-presentation of exogenous antigen on MHC class-I is a crucial process for generating a CD8⁺ T cell response, and is therefore an important design consideration in the development of T-cell-engaging vaccines against viruses, intracellular bacteria, and cancers. Here, we briefly summarize known cross-presentation pathways and highlight how synthetic vaccines can be engineered to enhance MHC-I presentation of exogenous peptide and protein antigens by professional antigen-presenting cells (APCs). In particular, we summarize how molecular engineering and nanotechnology are being harnessed to enhance antigen delivery to lymph nodes and to cross-presenting dendritic cells, to bypass endosomal trafficking of exogenous antigen to promote delivery of antigen to the cytosol of APCs, and to coordinate the delivery of antigen with immune-stimulating adjuvants that can act synergistically to augment antigen cross-presentation.

Figure 1

Pathways for MHC class-I antigen presentation. In the classical pathway, endogenous antigen is processed into peptides via the proteasome, followed by transport of peptides to the ER where they are loaded onto MHC-I molecules. In the vacuolar pathway, exogenous antigen is endocytosed, where it is degraded via endo-/lysosomal proteases and binds to MHC-I on the vesicle membrane. In the cytosolic pathway, antigen is endocytosed, but is then transported to the cytosol where it is degraded by the proteasome. In the phagosome-loading pathway, the degraded antigen is then transported back into the phagosome where it binds to MHC-I. In the ER-loading pathway, the antigen is transported via TAP into the ER lumen where it binds to MHC-I. Created with BioRender.com.

Figure 2

Nanoparticle vaccines can enhance LN and DC targeting. (a) After subcutaneous injection, a large fraction of small molecules and lower molecular weight free antigens will distribute directly to the circulation, whereas nanoparticles < 100 nm and antigen designed to bind to serum albumin will preferentially drain the injection site via lymphatic vessels and accumulate in LNs, where they can be endocytosed by CD8α⁺ DCs. (b) Nanoparticle vaccines can be designed to display targeting ligands specific for receptors on DCs, leading to enhanced uptake and cross-presentation. Created with BioRender.com.

Figure 3

Materials can be engineered to enhance endosomal escape of antigen for processing in the cytosol and presentation on MHC class-I molecules. Extracellular antigen that is endocytosed by APCs will be predominantly degraded in endo-/lysosomes and presented on MHC-II molecules. However, antigen loaded into carriers designed to disrupt endosomal membranes can promote the escape of antigen from endosomal confinement to the cytosol. A broad class of cationic materials have been designed to exploit the proton sponge mechanism, which relies on the capacity of a material to buffer the pH of the endosome, resulting in osmotic swelling and disruption of endosomal membrane integrity and the subsequent diffusion of contents into the cytosol. A second class of materials leverages protonizable groups to sense a drop in endosomal pH, triggering a change in conformation and/or solubility that confers a capacity for disrupting the endosomal membrane, thereby enabling endosomal escape and cytosolic delivery of antigen cargo. Both types of materials can be leveraged to promote cytosolic delivery of antigen to MHC class-I processing and presentation machinery. Created with BioRender.com.

Figure 4

Adjuvants can enhance cross-presentation through several mechanisms. Adjuvants can induce an innate immune response by binding to pattern-recognition receptors, such as STING or various TLRs, or by activating inflammasomes. Packaged co-delivery of immune-stimulating adjuvants with antigen can increase antigen uptake and retention, enhance expression of costimulatory molecules, and induce secretion of IFN-I and Th1 cytokines, which increases cross-presentation efficiency and leads to a more robust downstream CD8⁺ T cell response. Created with BioRender.com.