Orally Administered Exosomes Suppress Mouse Delayed-Type Hypersensitivity by Delivering miRNA-150 to Antigen-Primed Macrophage APC Targeted by Exosome-Surface Anti-Peptide Antibody Light Chains.

Katarzyna Nazimek,Philip Askenase,Tom Groot Kormelink,Krzysztof Bryniarski,Wlodzimierz Ptak

doi:10.3390/ijms21155540

Katarzyna Nazimek, Philip Askenase + Show 3 more

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https://doi.org/10.3390/ijms21155540

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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 are 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 similarly 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 an 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 treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration.

Highlights

Recent studies have shown that immune regulation in vivo is more diverse than previously appreciated
Their effect is similar to the exosomes induced in the T cells (Ts)-cells of Ag-tolerized mice, that endogenously acquired miRNA-150. This was termed “an alternate Ag-specific exosome-mediated suppression pathway” [10]. Results of these prior studies on contact sensitivity (CS) suppression led to the conclusion that in vivo these Ag-specific B1a cell-derived exosomes can associate with exogenous inhibitory non-exosomal miRNA, perhaps carried in vivo by RNA-binding argonaute proteins [4]
Such miRNA-150-associated exosomes were strongly inhibitory against CS effector cells [4]. It seemed that this miRNA likely was acquired from the freely circulating, extracellular pool of non-exosomal RNAs protected from RNases by chaperones like Argonaut proteins [4]

Summary

Introduction

Recent studies have shown that immune regulation in vivo is more diverse than previously appreciated. A unique antigen (Ag)-specificity of T cell immunosuppression was described previously in contact sensitivity (CS) induced by epicutaneous immunization of mice with reactive hapten [1,2,3,4,5]. This form of Ag-specific T cell tolerance is systemically generated by intravenous (IV) administration of high doses of hapten-conjugated syngeneic erythrocytes, followed by skin sensitization with the same reactive hapten. Exosome-mediated suppression was unequivocally confirmed by an in vivo experiment, showing that systemic administration of these exosomes to actively sensitized hosts at the peak of the hapten-specific effector T cell-mediated CS strongly reduced subsequent immune skin swelling responses measured for over four days [4]

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