Inflammatory Cytokine Induced Immunosuppression in Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSCs) are strongly immunosuppressive in vivo and in vitro in both animals and humans. Using our recently generated clones of MSCs derived from mouse bone marrow, we have shown that MSCs potently inhibit the T cell receptor (TCR)‐triggered proliferation and cytokine production by freshly‐isolated T cells. However, the molecular mechanisms controlling the immunosuppressive capacity of MSCs are unknown. We found that the immunosuppressive function of MSCs is elicited by IFNγ and the concomitant presence of any of three other proinflammatory cytokines, TNFα, IL‐1α or IL‐1β. 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 IFNγR1−/− mice. Blockade of chemokine receptors also abolished the immunosuppression. Wild‐type MSCs, but not IFNγR1−/− or iNOS−/− MSCs, prevented GVHD in mice, an effect reversed by anti‐IFNγ 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. We believe that a better understanding of the mechanisms through inflammatory cytokine activated‐MSCs mediate immunosuppression will lead to better clinical protocols for immune modulation.