Role for interferon-gamma 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)-gamma 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-gamma. The suppressive effect of IFN-gamma 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-gamma.
Krampera
Mauro
M
Department of Clinical and Experimental Medicine, University of Verona, Italy.
Cosmi
Lorenzo
L
Angeli
Roberta
R
Pasini
Annalisa
A
Liotta
Francesco
F
Andreini
Angelo
A
Santarlasci
Veronica
V
Mazzinghi
Benedetta
B
Pizzolo
Giovanni
G
Vinante
Fabrizio
F
Romagnani
Paola
P
Maggi
Enrico
E
Romagnani
Sergio
S
Annunziato
Francesco
F
D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology; D001854:Bone Marrow Cells / Q000502:physiology*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D013997:Time Factors
D015704:CD4 Antigens; D016827:CD8 Antigens; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma