Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype.
OBJECTIVE
Experimental evidence and preliminary clinical studies have demonstrated that human mesenchymal stem cells (MSC) have an important immune modulatory function in the setting of allogeneic hematopoietic stem cell (HSC) transplantation. We extended the evaluation of mechanisms responsible for the immune regulatory effect derived from the interaction of human MSC with cells involved in alloantigen-specific immune response in mixed lymphocyte culture (MLC).


METHODS
Dendritic cell (DC) differentiation, T- and natural killer (NK)-lymphocyte expansion, alloantigen-specific cytotoxic activity and differentiation of CD4+ T-cell subsets co-expressing CD25 and/or CTLA4 molecules were assessed, comparing the effect observed using third-party MSC with that obtained employing MSC autologous to the MLC responder.


RESULTS
We found that human MSC strongly inhibit alloantigen-induced DC1 differentiation, down-regulate alloantigen-induced lymphocyte expansion, especially that of CD8+ T cells and of NK lymphocytes, decrease alloantigen-specific cytotoxic capacity mediated by either cytotoxic T lymphocytes or NK cells and favor the differentiation of CD4+ T-cell subsets co-expressing CD25 and/or CTLA4. More effective suppressive activity on MLC-induced T-cell activation was observed when MSC were third-party, rather than autologous, with respect to MLC-responder cells.


CONCLUSIONS
Our results strongly suggest that MSC-mediated inhibition of alloantigen-induced DC1 differentiation and preferential activation of CD4+ CD25+ T-cell subsets with presumed regulatory activity represent important mechanisms contributing to the immunosuppressive activity of MSC. Collectively, these data provide immunological support for the use of MSC to prevent immune complications related to both HSC and solid organ transplantation and to the theory that MSC are universal suppressors of immune reactivity.
Maccario
Rita
R
Laboratorio di Immunologia dei Trapianti, Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia, Italy. r.maccario@smatteo.pv.it
Podestà
Marina
M
Moretta
Antonia
A
Cometa
Angela
A
Comoli
Patrizia
P
Montagna
Daniela
D
Daudt
Liane
L
Ibatici
Adalberto
A
Piaggio
Giovanna
G
Pozzi
Sarah
S
Frassoni
Francesco
F
Locatelli
Franco
F
D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002450:Cell Communication; D002454:Cell Differentiation; D000939:Epitopes; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007165:Immunosuppression Therapy; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology*
D000939:Epitopes; D007519:Isoantigens