Proposed mechanisms of action of MSCs. We propose that MSCs mediate their immunomodulatory effects by interacting with cells from both the innate (DC, pathways 2-4; NK cell, pathway 6) and adaptive immunity systems (T cell, pathways 1 and 5). MSC inhibition of TNF-α secretion and promotion of IL-10 secretion may affect DC maturation state and their functional properties, resulting in skewing the immune response toward in an anti-inflammatory/tolerant phenotype. Alternatively, when MSCs are present an inflammatory microenvironment, they inhibit IFN-γ secretion from T_H1 and NK cells and increase IL-4 secretion from T_H2 cells, thereby promoting a T_H1 → T_H2 shift. It is likely that MSCs also mediate their immunomodulatory actions by direct cell-cell contact as well as by secreted factors. Several MSC cell-surface molecules and secreted molecules are depicted. CCL indicates chemokine ligand; TCR, T-cell receptor.