Targeted immunomodulation using antigen-conjugated nanoparticles

Abstract

The growing prevalence of nanotechnology in the fields of biology, medicine, and the pharmaceutical industry is confounded by the relatively small amount of data on the impact of these materials on the immune system. In addition to concerns surrounding the potential toxicity of nanoparticle (NP)-based delivery systems, there is also a demand for a better understanding of the mechanisms governing interactions of NPs with the immune system. Nanoparticles can be tailored to suppress, enhance, or subvert recognition by the immune system. This 'targeted immunomodulation' can be achieved by delivery of unmodified particles, or by modifying particles to deliver drugs, proteins/peptides, or genes to a specific site. In order to elicit the desired, beneficial immune response, considerations should be made at every step of the design process: the NP platform itself, ligands, and other modifiers, the delivery route, and the immune cells that will encounter the conjugated NPs can all impact host immune responses.

FIGURE 1

Dendritic cells initiate T cell immunity in the lymph nodes. A mature DC encounters antigen in the lymph nodes where it processes and cross-presents the antigen in the context of peptide/MHC molecules to T cells. A T cell bearing a receptor (TCR) of cognate specificity to the presented peptide/MHC is induced by TCR stimulation (signal 1) to express CD40L, leading to activation of the DC through CD40 engagement. DC activation results in increased costimulation to the T cell through the B7/C28 pathway (signal 2). TCR stimulation in the presence of CD28 signaling results in T cell activation, IL-2 dependent proliferation, and differentiation into an effector T cell. The cytokine milieu directs T cell differentiation along one of the helper T cell (T_H) lineages.

FIGURE 2

Methods of displaying antigen on the particle surface. A) Chemical conjugation uses chemical crosslinkers or biotin-streptavidin cross-bridges to link the desired peptide to the NP surface. B) Genetic insertion results in recombinant particles in which the peptide of interest is inserted into a coat protein and displayed on the surface of a VLP following successful translation.

FIGURE 3

The uptake of Ag-NP by splenic marginal zone macrophages leads to the induction of T cell tolerance. A) Ag-NP in the spleen are phagocytosed by marginal zone macrophages (MΦ) through the scavenger receptor MARCO, leading to a tolerogenic phenotype and an increase in PD-L1 and immunoregulatory cytokine expression. B) The immunoregulatory milieu supports the induction and/or activation of Foxp3⁺ Tregs that may limit the ability of splenic APCs to prime naïve T cells by producing immunosuppressive cytokines and by CTLA-4-mediated trans-endocytosis of CD80/CD86 molecules. Cross-presentation of the antigen to a T cell (signal 1) in the absence of costimulation (signal 2) causes abortive activation and defective IL-2 production, leading to the induction of adaptive or clonal T cell anergy in naïve and differentiated effector T cells, respectively.