HLA-G5 secretion by Human Mesenchymal Stem Cells Is Required to Suppress T-lymphocyte and NK Function and to Induce CD4⁺CD25^highFOXP3⁺ Regulatory T Cells

¹ Inserm U645, IFR 133, Universite de Franche-Comte, Etablissement Français du Sang Bourgogne-Franche-Comte, Besancon, France.
² Service de Recherches en Hemato-Immunologie, CEA-DSV-DRM, Hopital Saint-Louis, IUH, Paris, France.
³ Inserm U645, IFR 133, Universite de Franche-Comte, Etablissement Français du Sang Bourgogne-Franche-Comte, Besancon, France.; Département d'orthopedie, CHU Jean Minjoz, Besancon, France.

^* To whom correspondence should be addressed. E-mail: fdeschaseaux{at}chu-besancon.fr.

	Abstract

Adult bone marrow-derived mesenchymal stem cells (MSCs) are multipotent cells which are the subject of intense investigations in regenerative medicine. In addition, MSCs possess immunomodulatory properties with therapeutic potential to prevent graft-versus-host disease (GvHD) in allogeneic hematopoietic cell transplantation (HCT). Indeed, MSCs can inhibit NK function, modulate dendritic cell maturation, and suppress allogeneic T cell response. Here, we report that the non classical HLA class-I molecule HLA-G is responsible for MSCs immunomodulatory properties. Our data show that MSCs secrete the soluble isoform HLA-G5 and that such secretion is IL-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. Further, we demonstrate that in addition to their action on adaptive immune system, MSCs through HLA-G5 affects the innate immunity by inhibiting both NK cell-mediated cytolysis and IFN- secretion. Our results provide evidences that HLA-G5 secreted by MSCs is critical to their suppressive functions and should contribute to improve clinical therapeutic trials using MSCs to prevent GvHD.

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