Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide

Cell Stem Cell. 2008 Feb 7;2(2):141-50. doi: 10.1016/j.stem.2007.11.014.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cells, Cultured
  • Chemokines / physiology*
  • Cytokines / pharmacology
  • Graft vs Host Disease / prevention & control
  • Hypersensitivity, Delayed / prevention & control
  • Immune Tolerance / immunology*
  • Interferon-gamma / pharmacology
  • Mesenchymal Stem Cells / immunology*
  • Mice
  • Mice, Knockout
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase Type II / genetics
  • Receptors, Interferon / genetics

Substances

  • Chemokines
  • Cytokines
  • Receptors, Interferon
  • interferon gamma receptor
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase Type II