Role for Interferon‐γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA‐unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell‐activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contact‐dependent and required the presence of interferon (IFN)‐γ produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN‐γ. The suppressive effect of IFN‐γ was related to its ability to stimulate the production by MSCs of indoleamine 2,3‐dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft‐versus‐host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell– derived IFN‐γ.

[1]  D. Couriel,et al.  Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management , 2004, Cancer.

[2]  M. Pittenger,et al.  Human mesenchymal stem cells modulate allogeneic immune cell responses. , 2005, Blood.

[3]  J. Myśliwska,et al.  CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. , 2004, Clinical immunology.

[4]  W. Mars,et al.  Bone marrow as a potential source of hepatic oval cells. , 1999, Science.

[5]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[6]  N. Mahmud,et al.  Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo. , 2001, Human gene therapy.

[7]  P. Bianco,et al.  Marrow stromal stem cells. , 2000, The Journal of clinical investigation.

[8]  C. Verfaillie,et al.  Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. , 2001, Blood.

[9]  L. Cosmi,et al.  Reversal of human allergen-specific CRTH2+ T(H)2 cells by IL-12 or the PS-DSP30 oligodeoxynucleotide. , 2001, The Journal of allergy and clinical immunology.

[10]  O. Ringdén,et al.  Mesenchymal Stem Cells Inhibit and Stimulate Mixed Lymphocyte Cultures and Mitogenic Responses Independently of the Major Histocompatibility Complex , 2003, Scandinavian journal of immunology.

[11]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[12]  O. Ringdén,et al.  Mesenchymal Stem Cells Inhibit the Expression of CD25 (Interleukin‐2 Receptor) and CD38 on Phytohaemagglutinin‐Activated Lymphocytes , 2004, Scandinavian journal of immunology.

[13]  E. Guinan,et al.  Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation , 2003, Transplantation.

[14]  L. Cosmi,et al.  Phenotype, Localization, and Mechanism of Suppression of CD4+CD25+ Human Thymocytes , 2002, The Journal of experimental medicine.

[15]  H. Blau,et al.  From marrow to brain: expression of neuronal phenotypes in adult mice. , 2000, Science.

[16]  I. Black,et al.  Adult rat and human bone marrow stromal cells differentiate into neurons , 2000, Journal of neuroscience research.

[17]  L. Cosmi,et al.  Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. , 2003, Blood.

[18]  S. Mckercher,et al.  Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. , 2000, Science.

[19]  E. Lam,et al.  Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. , 2005, Blood.

[20]  Elizabeth Simpson,et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. , 2003, Blood.

[21]  A. Caplan,et al.  Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5‐azacytidine , 1995, Muscle & nerve.

[22]  I. Weissman,et al.  Extrathymic maturation of alpha beta T cells from hemopoietic stem cells. , 1995, Journal of immunology.

[23]  Fridenshteĭn AIa.  Stromal bone marrow cells and the hematopoietic microenvironment , 1982 .

[24]  D. Keskin,et al.  Potential Regulatory Function of Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase , 2002, Science.

[25]  R. Beninger,et al.  Enhancement of 7-nitro indazole-induced inhibition of brain nitric oxide synthase by norharmane , 1995, Neuroscience Letters.

[26]  R. Schwartz,et al.  Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. , 2002, The Journal of clinical investigation.

[27]  M. Labopin,et al.  Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. Kawamura,et al.  Evidence for migration of donor bone marrow stromal cells into recipient thymus after bone marrow transplantation plus bone grafts: A role of stromal cells in positive selection. , 2000, Experimental hematology.

[29]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[30]  A. Globerson,et al.  Selective adhesion of immature thymocytes to bone marrow stromal cells: relevance to T cell lymphopoiesis. , 1996, Experimental hematology.

[31]  J. Bonnefoy,et al.  Annexin V used for measuring apoptosis in the early events of cellular cytotoxicity. , 1999, Cytometry.

[32]  Paul D. Kessler,et al.  Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart , 2002, Circulation.

[33]  M. Sono,et al.  1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. , 1991, Archives of biochemistry and biophysics.

[34]  A. Fridenshteĭn.  [Stromal bone marrow cells and the hematopoietic microenvironment]. , 1982, Arkhiv patologii.

[35]  U. Grohmann,et al.  Modulation of tryptophan catabolism by regulatory T cells , 2003, Nature Immunology.

[36]  S. Gerson,et al.  Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[38]  L. Cosmi,et al.  CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease , 2000 .

[39]  O. Ringdén,et al.  Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. , 2005, Experimental cell research.

[40]  Ulrich Göbel,et al.  bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 20, 2013. For personal use , 2004 .

[41]  G. Damonte,et al.  Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase , 2002, The Journal of experimental medicine.

[42]  O. Bagasra,et al.  Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  C. Carlo-Stella,et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. , 2002, Blood.

[44]  L. Cosmi,et al.  Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. , 2004, Blood.

[45]  O. Ringdén,et al.  Immunologic properties of human fetal mesenchymal stem cells. , 2004, American journal of obstetrics and gynecology.

[46]  O. Ringdén,et al.  Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells , 2003, Transplantation.

[47]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[48]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[49]  Kevin McIntosh,et al.  Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. , 2002, Experimental hematology.

[50]  E. Jenkinson,et al.  An Essential Role for Thymic Mesenchyme in Early T Cell Development , 2000, The Journal of experimental medicine.

[51]  F. Barry,et al.  Mesenchymal stem cells: stealth and suppression. , 2001, Cancer journal.

[52]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.