Orally Administered Exosomes Alleviate Mouse Contact Dermatitis through Delivering miRNA-150 to Antigen-Primed Macrophages Targeted by Exosome-Surface Antibody Light Chains

Abstract

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes induced CD3⁺CD8⁺ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral administration. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides, suggesting that exosome-coating FLC target APCs by binding to Ag-major histocompatibility complexes. This renders APCs able to inhibit DTH effector T cells. Thus, our studies described a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that are particularly effective after oral administration.