Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-γ and tumor necrosis factor-α stimulation.
OBJECTIVE
Mesenchymal stromal cells (MSCs) suppress T-cell proliferation, especially after activation with inflammatory cytokines. We compared the dynamic action of unprimed and interferon (IFN)-γ plus tumor necrosis factor (TNF)-α-pretreated human bone marrow-derived MSCs on resting or activated T cells.


METHODS
MSCs were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) at high MSC-to-PBMC ratios in the absence or presence of concomitant CD3/CD28-induced T-cell activation. The kinetic effects of MSCs on cytokine production and T-cell proliferation, cell cycle and apoptosis were assessed.


RESULTS
Unprimed MSCs increased the early production of IFN-γ and interleukin (IL)-2 by CD3/CD28-activated PBMCs before suppressing T-cell proliferation. In non-activated PBMC co-cultures, low levels of IL-2 and IL-10 synthesis were observed with MSCs in addition to low levels of CD69 expression by T cells and no T-cell proliferation. MSCs also decreased apoptosis in resting and activated T cells and inhibited the transition of these cells into the sub-G0/G1 and the S phases. With inhibition of indoleamine 2,3 dioxygenase, MSCs increased CD3/CD28-induced T-cell proliferation. After priming with IFN-γ plus TNF-α, MSCs were less potent at increasing cytokine production by CD3/CD28-activated PBMCs and more effective at inhibiting T-cell proliferation but had preserved anti-apoptotic functions.


CONCLUSIONS
Unprimed MSCs induce a transient increase in IFN-γ and IL-2 synthesis by activated T cells. Pre-treatment of MSCs with IFN-γ plus TNF-α may increase their effectiveness and safety in vivo.
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Jessica
J
Cuerquis
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Raphaëlle
R
Romieu-Mourez
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Moïra
M
François
Division of Hematology and Chronic Viral Illness Service, Royal Victoria Hospital, Montreal, Quebec, Canada.
Jean-Pierre
JP
Routy
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Yoon Kow
YK
Young
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Jing
J
Zhao
Lady Davis Institute for Medical Research and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada; Department of Surgery, Division of Surgical Research, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montreal, Quebec, Canada. Electronic address: nicoletta.eliopoulos@mcgill.ca.
Nicoletta
N
Eliopoulos
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D016207:Cytokines; D018836:Inflammation Mediators
T cells; cytokines; human; mesenchymal stromal cells