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

Stem Cells. 2008 Jan;26(1):212-22. doi: 10.1634/stemcells.2007-0554. Epub 2007 Oct 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / immunology
  • Adult Stem Cells / metabolism
  • Blotting, Western
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • CD4 Antigens / metabolism
  • Cell Communication
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • HLA Antigens / metabolism*
  • HLA-G Antigens
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Interferon-gamma
  • Interleukin-10
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Culture Test, Mixed
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / metabolism*
  • Microscopy, Confocal
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*


  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HLA Antigens
  • HLA-G Antigens
  • Histocompatibility Antigens Class I
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-10
  • Interferon-gamma