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

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. ### Competing Interest Statement The authors have declared no competing interest. * Ab : Antibody Ag : Antigen APC : Antigen-presenting cell CAR : Chimeric antigen receptor CS : Contact sensitivity DTH : Delayed-type hypersensitivity ELISA : Enzyme-linked immunosorbent assay exRNA : Extracellular ribonucleic acid EVs : Extracellular vesicles FLC : Free light chains ID : Intradermal IP : Intraperitoneal IV : Intravenous KLH : Keyhole limpet hemocyanin OVA : Ovalbumin OVA-RBC : Ovalbumin-coupled red blood cells OX : Oxazolone PO : Per os, oral administration RBC : Red blood cells TNP : Trinitrophenol Treg cell : Regulatory T cell Ts cell : Suppressor T cell WT : Wild type