title: Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells.
abstract: 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(high)FOXP3(+) 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-gamma 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.
authors.affiliation: Institut 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.
authors.forename: Zohair
authors.initials: Z
authors.lastname: Selmani
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Naji
authors.forename: Ines
authors.initials: I
authors.lastname: Zidi
authors.forename: Benoit
authors.initials: B
authors.lastname: Favier
authors.forename: Emilie
authors.initials: E
authors.lastname: Gaiffe
authors.forename: Laurent
authors.initials: L
authors.lastname: Obert
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
authors.forename: Philippe
authors.initials: P
authors.lastname: Saas
authors.forename: Pierre
authors.initials: P
authors.lastname: Tiberghien
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouas-Freiss
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.forename: Frederic
authors.initials: F
authors.lastname: Deschaseaux
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002450:Cell Communication; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma; D016753:Interleukin-10; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma