Mesenchymal stem cells (MSCs) can become potently immunosuppressive through unknown mechanisms. We found that the immunosuppressive function of MSCs is elicited by IFNgamma and the concomitant presence of any of three other proinflammatory cytokines, TNFalpha, IL-1alpha, or IL-1beta. These cytokine combinations provoke the expression of high levels of several chemokines and inducible nitric oxide synthase (iNOS) by MSCs. Chemokines drive T cell migration into proximity with MSCs, where T cell responsiveness is suppressed by nitric oxide (NO). This cytokine-induced immunosuppression was absent in MSCs derived from iNOS(-/-) or IFNgammaR1(-/-) mice. Blockade of chemokine receptors also abolished the immunosuppression. Administration of wild-type MSCs, but not IFNgammaR1(-/-) or iNOS(-/-) MSCs, prevented graft-versus-host disease in mice, an effect reversed by anti-IFNgamma or iNOS inhibitors. Wild-type MSCs also inhibited delayed-type hypersensitivity, while iNOS(-/-) MSCs aggravated it. Therefore, proinflammatory cytokines are required to induce immunosuppression by MSCs through the concerted action of chemokines and NO.

Cell–cell adhesion mediated by ICAM-1 and VCAM-1 is critical for T cell activation and leukocyte recruitment to the inflammation site and, therefore, plays an important role in evoking effective immune responses. However, we found that ICAM-1 and VCAM-1 were critical for mesenchymal stem cell (MSC)-mediated immunosuppression. When MSCs were cocultured with T cells in the presence of T cell Ag receptor activation, they significantly upregulated the adhesive capability of T cells due to the increased expression of ICAM-1 and VCAM-1. By comparing the immunosuppressive effect of MSCs toward various subtypes of T cells and the expression of these adhesion molecules, we found that the greater expression of ICAM-1 and VCAM-1 by MSCs, the greater the immunosuppressive capacity that they exhibited. Furthermore, ICAM-1 and VCAM-1 were found to be inducible by the concomitant presence of IFN-γ and inflammatory cytokines (TNF-α or IL-1). Finally, MSC-mediated immunosuppression was significantly reversed in vitro and in vivo when the adhesion molecules were genetically deleted or functionally blocked, which corroborated the importance of cell–cell contact in immunosuppression by MSCs. Taken together, these findings reveal a novel function of adhesion molecules in immunoregulation by MSCs and provide new insights for the clinical studies of antiadhesion therapies in various immune disorders.

Bone marrow-derived mesenchymal stem cells (MSCs) hold great promise for treating immune disorders because of their immunoregulatory capacity, but the mechanism remains controversial. As we show here, the mechanism of MSC-mediated immunosuppression varies among different species. Immunosuppression by human-or monkey-derived MSCs is mediated by indoleamine 2,3-dioxygenase (IDO), whereas mouse MSCs utilize nitric oxide, under the same culture conditions. When the expression of IDO and inducible nitric oxide synthase (iNOS) were examined in human and mouse MSCs after stimulation with their respective inflammatory cytokines, we found that human MSCs expressed extremely high levels of IDO, and very low levels of iNOS, whereas mouse MSCs expressed abundant iNOS and very little IDO. Immunosuppression by human MSCs was not intrinsic, but was induced by inflammatory cytokines and was chemokine-dependent, as it is in mouse. These findings provide critical information about the immunosuppression of MSCs and for better application of MSCs in treating immune disorders.

SUMMARY Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. These tumor-resident MSCs are known to affect tumor growth, but the mechanisms are largely unknown. We found that MSCs isolated from spontaneous lymphomas in mouse (L-MSCs) strikingly enhanced tumor growth in comparison to bone marrow MSCs (BM-MSCs). L-MSCs contributed to greater recruitment of CD11b+Ly6C+ monocytes, F4/80+ macrophages, and CD11b+Ly6G+ neutrophils to the tumor. Depletion of monocytes/macrophages, but not neutrophils, completely abolished tumor promotion of L-MSCs. Furthermore, L-MSCs expressed high levels of CCR2 ligands, and monocyte/macrophage accumulation and L-MSC-mediated tumor promotion were largely abolished in CCR2−/− mice. Intriguingly, TNFα-pretreated BM-MSCs mimicked L-MSCs in their chemokine production profile and ability to promote tumorigenesis of lymphoma, melanoma, and breast carcinoma. Therefore, our findings demonstrate that, in an inflammatory environment, tumor-resident MSCs promote tumor growth by recruiting monocytes/macrophages.

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