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TISSUE-SPECIFIC STEM CELLS

Human Leukocyte Antigen-G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4⁺CD25^highFOXP3⁺ Regulatory T Cells

^aInstitut National de la Santé et de la Recherche Médicale U645, IFR 133, Universite de Franche-Comte, Etablissement Français du Sang Bourgogne-Franche-Comte, Besançon, France;
^bService de Recherches en Hemato-Immunologie, CEA-DSV-DRM, Hopital Saint-Louis, IUH, Paris, France;
^cDépartement d'Orthopedie, CHU Jean Minjoz, Besançon, France

Key Words. Immunosuppression • Human leukocyte antigen-G • Mesenchymal stem cells • Interleukin-10 • Regulatory T cells

Correspondence: Correspondence: Frederic Deschaseaux, Ph.D., INSERM U645, 240 route de Dole, 25 000 Besançon, France. Telephone: 33-0-3-81-52-33-00; Fax: 33-0-3-81-52-64-80; e-mail: fdeschaseaux{at}chu-besancon.fr

Received on July 11, 2007; accepted for publication on September 26, 2007.

First published online in STEM CELLS EXPRESS  October 11, 2007.


Adult bone marrow-derived mesenchymal stem cells (MSCs) are multipotent cells that are the subject of intense investigation in regenerative medicine. In addition, MSCs possess immunomodulatory properties with therapeutic potential to prevent graft-versus-host disease (GvHD) in allogeneic hematopoietic cell transplantation. Indeed, MSCs can inhibit natural killer (NK) function, modulate dendritic cell maturation, and suppress allogeneic T-cell response. Here, we report that the nonclassic human leukocyte antigen (HLA) class I molecule HLA-G is responsible for the immunomodulatory properties of MSCs. Our data show that MSCs secrete the soluble isoform HLA-G5 and that such secretion is interleukin-10-dependent. Moreover, cell contact between MSCs and allostimulated T cells is required to obtain a full HLA-G5 secretion and, as consequence, a full immunomodulation from MSCs. Blocking experiments using neutralizing anti-HLA-G antibody demonstrate that HLA-G5 contributes first to the suppression of allogeneic T-cell proliferation and then to the expansion of CD4⁺CD25^highFOXP3⁺ regulatory T cells. Furthermore, we demonstrate that in addition to their action on the adaptive immune system, MSCs, through HLA-G5, affect innate immunity by inhibiting both NK cell-mediated cytolysis and interferon- secretion. Our results provide evidence that HLA-G5 secreted by MSCs is critical to the suppressive functions of MSCs and should contribute to improving clinical therapeutic trials that use MSCs to prevent GvHD.

Disclosure of potential conflicts of interest is found at the end of this article.

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