Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6.
OBJECTIVE
Mesenchymal stromal cells (MSC) have been shown to possess immunomodulatory functions and proposed as a tool for managing or preventing graft-versus-host disease (GvHD) as well as promoting clinical transplantation tolerance. We investigated the capacity of human bone marrow (BM) MSC to modulate the proliferation of T cells obtained from peripheral blood (PB) and umbilical cord blood (CB). We addressed the importance of the MSC:T-cell ratio, requirement for cell contact and impact of soluble factors on the MSC-mediated effects. We also analyzed whether regulatory T cells could be modulated by MSC in co-cultures.


METHODS
The effect of different MSC concentrations on T-cell proliferation induced by allogeneic, mitogenic or CD3/CD28 stimulation was analyzed using bromodeoxyuridine (BrdU) incorporation and carboxyfluorescein diacetate-succinimidyl ester (CFDA-SE) labeling. The level of regulatory T cells was assessed using quantitative real-time polymerase chain reaction (PCR) and flow cytometry analysis.


RESULTS
MSC induced a dose- and contact-dependent inhibition of T-cell proliferation but lymphocytes from CB and PB were differentially affected. At low concentrations, MSC supported both CB and PB T-cell proliferation, rather than inhibiting their proliferation. This supportive effect was contact independent and soluble factors such interleukin-6 (IL-6) appeared to be involved. Interestingly, among the expanded T-cell population in both CB and PB, regulatory T cells were increased and were a part of the new cells promoted by MSC at low doses.


CONCLUSIONS
MSC represent an attractive tool for reducing the lymphocyte response by inhibiting T-cell activation and proliferation as well as promoting tolerance by maintaining and promoting the expansion of regulatory cells. Nevertheless, the dual ability of MSC to either sustain or suppress T-cell proliferation according to conditions should be considered in the context of clinical applications.
Najar
Mehdi
M
Laboratory of Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Brussels, Belgium.
Rouas
Redouane
R
Raicevic
Gordana
G
Boufker
Hichame Id
HI
Lewalle
Philippe
P
Meuleman
Nathalie
N
Bron
Dominique
D
Toungouz
Michel
M
Martiat
Philippe
P
Lagneaux
Laurence
L
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D015704:CD4 Antigens / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008934:Mitogens / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
D015704:CD4 Antigens; D017077:Culture Media, Conditioned; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D053699:Interleukin-7 Receptor alpha Subunit; D008934:Mitogens; D051997:ADP-ribosyl Cyclase 1