Mesenchymal stromal cell exosome–enhanced regulatory T-cell production through an antigen-presenting cell–mediated pathway

Abstract Background aims The immunomodulatory property of mesenchymal stromal cell (MSC) exosomes is well documented. On the basis of our previous report that MSC exosomes increased regulatory T-cell (Treg) production in mice with allogenic skin graft but not in ungrafted mice, we hypothesize that an activated immune system is key to exosome-mediated Treg production. Methods To test our hypothesis, MSC exosomes were incubated with mouse spleen CD4 + T cells that were activated with either anti-CD3/CD28 mAbs or allogenic antigen-presenting cell (APC)-enriched spleen CD11c + cells to determine whether production of mouse CD4 + CD25 + T cells or CD4 + CD25 + Foxp3 + Tregs could be induced. MSC exosomes were also administered to the lethal chimeric human-SCID mouse model of graft-versus-host disease (GVHD) in which human peripheral blood mononuclear cells were infused into irradiated NSG mice to induce GVHD. Results We report here that MSC exosome–induced production of CD4 + CD25 + T cells or CD4 + CD25 + Foxp3 + Tregs from CD4 + T cells activated by allogeneic APC-enriched CD11C + cells but not those activated by anti-CD3/CD28 mAbs. This induction was exosome- and APC dose–dependent. In the mouse GVHD model in which GVHD was induced by transplanted human APC-stimulated human anti-mouse CD4 + T cell effectors, MSC exosome alleviated GVHD symptoms and increased survival. Surviving exosome-treated mice had a significantly higher level of human CD4 + CD25 + CD127 low/– Tregs than surviving mice treated with Etanercept, a tumor necrosis factor inhibitor. Conclusions MSC exosome enhanced Treg production in vitro and in vivo through an APC-mediated pathway.