MSCs have immunomodulatory properties that are among the most intriguing aspects of their biology . Francesco Dazzi reported, in a murine model, that MSCs inhibit the division of stimulated T cells by preventing their entry into the S phase of the cell cycle and by mediating an irreversible G0/G1 phase arrest . MSCs also induced arrest of T-cell division in mixed lymphocyte reactions (MLRs); this effect was irreversible upon removal of the MSCs. In primate  and human [22, 23] models reversibility is observed. In contrast to the strong inhibitory effects of MSCs on T-cell proliferation, there were only relatively minor and reversible effects on the T-cell effector function, as measured by IFN-γ production, and no effects on T-cell activation, based on CD25 and CD69 surface expression. Dazzi summarized these differential immunomodulatory effects of MSCs on T-cell functions as 'split tolerance'. The T-cell inhibition does not appear to be antigen specific , works across HLA barriers, and targets primary and secondary responses . Interestingly, the T-cell proliferation was found to be inhibited across strain (allo-) and species (xeno-) barriers. Jones, however, showed that immunosuppression may be not only be an intrinsic property of MSCs in particular but also of mature and immature stromal cells in general, because osteoblasts have similar antiproliferative effect (unpublished data).
Vito Pistoia outlined that MSCs also have an effect on B cells. In vitro, B-cell proliferation is inhibited by MSCs in a dose-dependent manner, with maximum inhibition observed at a B-cell/MSC ratio of 1:1 . Soluble factors are involved. B-cell inhibition by MSCs is attributable to blockade in G0/G1 phases of the cell cycle similar to T cells. MSCs also reduce the expression of chemokine receptors and immunoglobulin production by stimulated B cells. MSCs, however, do not appear to alter surface molecules that are involved in stimulatory cell cooperation (HLA-DR, CD40 and B7 family) or to inhibit the expression of tumour necrosis factor (TNF), IFN-γ, IL-4 and IL-10.
Willem Fibbe showed that MSCs also inhibit the differentiation of monocytes into immature dendritic cells (DCs) . Dazzi and coworkers have confirmed this observation and demonstrated that MSCs mediate a block of the monocyte cell cycle at the G0 phase in this case also . Cell contact between MSCs and DCs is not required and soluble factors that mediate inhibition of differentiation are produced as a result of crosstalk between MSCs and DCs. Expression by DCs of costimulatory molecules is downregulated, and DCs exhibit impaired cytokine production and a reduced ability to stimulate T cells. MSCs also inhibit the IL-1 and CD40 ligand induced maturation of immature into mature DCs. Aggarwal and Pittenger  also demonstrated that MSCs cause immature DCs to decrease TNF-α and mature DCs to increase IL-10 secretion.
It has been suggested that natural killer (NK) cell function is also affected by MSCs, with downregulation of IFN-γ secretion , but in vitro data reported by Le Blanc and coworkers  suggest that neither NK cell nor cytotoxic T lymphocyte (CTL) lysis is affected by MSCs. On the other hand, the same group from the Karolinska Institute showed that MSCs reduce the formation of CTLs via a soluble factor, but they are not themselves subject to immune recognition by CTLs and allogeneic NK cells .
Recently reported data  suggest that MSCs significantly inhibit IL-2 stimulated proliferation of resting NK cells, but they only partly impair activated NK cell proliferation. The same group showed that IL-2 activated NK cells lyse autologous and allogeneic MSCs, which is a property not seen with freshly isolated NK cells. Cell-cell contact and soluble factors such as transforming growth factor-β and prostaglandin (PG)E2 are responsible for this effect . Moreover, when MSCs were exposed to IFN-γ lysis was reduced, presumably because of upregulation of HLA class I molecules on the MSC surface. The NK receptors activating the lysis included NKp30 and NKG2D, for which MSCs have ligands. This has also been demonstrated by another group ; however, that group did not demonstrate protection by expression of HLA class I molecules on the MSCs.
Several speakers addressed the issue of the role of soluble factors in the immunomodulatory properties of MSCs. Human MSCs caused T-helper-1 cells to decrease IFN-γ and T-helper-2 cells to increase IL-4 secretion. Addition of IFN-γ to MSCs in vitro increases their antiproliferative effect in a MLR .
A critical effect of IL-6 in MLRs was stressed by Jorgenson, who showed that IL-6 was released by MSCs and that, if blocked with anti-IL-6 antibodies, normal T-cell proliferation was restored in an MLR. Fibbe also showed in DCs that the MSC-mediated immunosuppression was prevented by addition of anti-IL-6 and anti-macrophage colony stimulating factor antibodies, at least in part . TNF-α also reversed the immunosuppressive effect of MSCs on the MLR.
Previous experiments by Di Nicola and coworkers  have suggested that two soluble factors, namely hepatocyte growth factor and TGF-β, were also involved. The addition of anti-HGF and anti-TGF-β partially restored the proliferation of CD2+ cells in the presence of MSCs. However, others were unable to reproduce these results .
Indoleamine 2', 3'-dioxygenase (IDO) is an enzyme that is induced by IFN-γ on the surface of antigen-presenting cells and then converts tryptophane to kynurenine. The degradation of tryptophane, as an amino acid that is essential for lymphocyte proliferation, was suggested to inhibit T-cell proliferation . The same mechanism has been shown to operate for MSCs as well . However, interpretation of these effects is complicated by the fact that the immunosuppressive kinetics of MSCs were found not to correspond to those of IDO expression and tryptophane depletion [37, 38]. Recently, failure to achieve significant restoration of T-cell proliferation via tryptophane addition was reported and attributed to the production of T-cell inhibitory kynurenine metabolites, which may have immunosuppressive properties in their own right [39, 40]. Inhibitors of PGE2 synthesis mitigated the overall immunosuppressive effects in co-cultures, suggesting that PGE2 may also play an important role in the immune modulation . However, others have not detected significant reversal in T-cell proliferation when using PGE2 synthesis inhibitors or tryptophane . Jorgenson investigated a murine MSC line and found PGE2, but not IDO, to be involved in the immunosuppressive effects.
MSCs not only appear to downregulate the immunoreactivity of a variety of effector cells, but also they themselves are believed to escape immune rejection. MSCs are not targets for CD8+ cytotoxic lymphocytes or KIR-ligand mismatched NK cells in vitro [34, 38, 41, 42]. After in utero transplantation into sheep, human MSCs persist in the long term and demonstrate site-specific differentiation .