Mechanisms mediating immunomodulation. MSCs and their derived extracellular vesicles (EVs) exert their effect on innate (NK, neutrophils, monocytes, and macrophages) and adaptive (B and T cells) immune systems, as well as dendritic cells (DCs) through cell-to-cell interactions and several immunomodulatory factors. Activated T cells activate resting MSCs, which in turn facilitate the recruitment of helper and effector T cells via CXCL9 and CXCL10. Several immunomodulatory factors (TGF-β, PGE2, and HLA-G5) and membrane-bound molecules (PD-L1) suppress CD4+ and CD8+ T cell proliferation and induce the polarization of CD4+ T cells towards Th17 cells. NO and IDO released by MSCs act on the suppression of CD8+ T cell proliferation, cytokine production, and cytotoxicity. MSCs support the development of Treg populations via IL-10, TGF-β, and HLA-G5. In the context of B cells, MSCs inhibit activation, proliferation, chemokine receptor expression, and differentiation to antibody-secreting plasma cells. MSCs suppress naïve macrophage polarization to proinflammatory M1 macrophage and then favor anti-inflammatory M2 polarization. IL-6 secreted by MSCs suppresses neutrophil apoptosis and respiratory burst.