Fig. 1.

Mechanisms of MSC-mediated immunosuppression. Licensing of MSCs is essential to induce their immunosuppressive effects and can occur via stimulation with cytokines such as IFN-γ, TNF-α, IL-1β or TLR ligands present in the inflammatory microenvironment, or via direct cell–cell contact with activated cytotoxic T and NK cells. 1) MSCs licensed by soluble factors become potent immunomodulatory agents by producing an immunosuppressive secretome characterized by molecules such as IDO, PGE2, TGF-β, TSG-6, IL-10, IL-6, HGF, soluble HLA-G and IL-1RA and the activation of PD-1/PD-L1 and Fas/FasL signaling. In addition, the combination of soluble molecules present in the microenvironment can activate apoptotic pathways in MSCs and their subsequent efferocytosis by monocytes/macrophages. 2) MSCs licensed by cytotoxic cells undergo rapid caspase-dependent apoptosis and are efferocytosed by monocytes/macrophages, which become anti-inflammatory cells releasing similar immunosuppressive molecules. Apoptotic MSCs further contribute to immunosuppression by releasing caspase-dependent immunomodulatory factors. These licensing mechanisms result in efficient immunomodulation through the inhibition of T cells, NK cells, and DCs, M2 macrophage polarization and Treg expansion. Figure generated using BioRender.com