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

Laboratorio di Immunologia dei Trapianti, Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia, Italy. r.maccario@smatteo.pv.it

BACKGROUND AND OBJECTIVES: 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). DESIGN AND 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. INTERPRETATION AND 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.

This article has been cited by other articles:

				F. Casiraghi, N. Azzollini, P. Cassis, B. Imberti, M. Morigi, D. Cugini, R. A. Cavinato, M. Todeschini, S. Solini, A. Sonzogni, et al. Pretransplant Infusion of Mesenchymal Stem Cells Prolongs the Survival of a Semiallogeneic Heart Transplant through the Generation of Regulatory T Cells J. Immunol., September 15, 2008; 181(6): 3933 - 3946. [Abstract] [Full Text] [PDF]

				L. da Silva Meirelles, A. I. Caplan, and N. B. Nardi In Search of the In Vivo Identity of Mesenchymal Stem Cells Stem Cells, September 1, 2008; 26(9): 2287 - 2299. [Abstract] [Full Text] [PDF]

				H. Karlsson, S. Samarasinghe, L. M. Ball, B. Sundberg, A. C. Lankester, F. Dazzi, M. Uzunel, K. Rao, P. Veys, K. Le Blanc, et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses Blood, August 1, 2008; 112(3): 532 - 541. [Abstract] [Full Text] [PDF]

				R. Atoui, D. Shum-Tim, and R. C.J. Chiu Myocardial regenerative therapy: immunologic basis for the potential "universal donor cells". Ann. Thorac. Surg., July 1, 2008; 86(1): 327 - 334. [Abstract] [Full Text] [PDF]

				B. Parekkadan, A. W. Tilles, and M. L. Yarmush Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Autoimmune Enteropathy Independently of Regulatory T Cells Stem Cells, July 1, 2008; 26(7): 1913 - 1919. [Abstract] [Full Text] [PDF]

				F. Morandi, L. Raffaghello, G. Bianchi, F. Meloni, A. Salis, E. Millo, S. Ferrone, V. Barnaba, and V. Pistoia Immunogenicity of Human Mesenchymal Stem Cells in HLA-Class I-Restricted T-Cell Responses Against Viral or Tumor-Associated Antigens Stem Cells, May 1, 2008; 26(5): 1275 - 1287. [Abstract] [Full Text] [PDF]

				P. Comoli, F. Ginevri, R. Maccario, M. A. Avanzini, M. Marconi, A. Groff, A. Cometa, M. Cioni, L. Porretti, W. Barberi, et al. Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1196 - 1202. [Abstract] [Full Text] [PDF]

				Y.-P. Li, S. Paczesny, E. Lauret, S. Poirault, P. Bordigoni, F. Mekhloufi, O. Hequet, Y. Bertrand, J.-P. Ou-Yang, J.-F. Stoltz, et al. Human Mesenchymal Stem Cells License Adult CD34+ Hemopoietic Progenitor Cells to Differentiate into Regulatory Dendritic Cells through Activation of the Notch Pathway J. Immunol., February 1, 2008; 180(3): 1598 - 1608. [Abstract] [Full Text] [PDF]

				M. Magatti, S. De Munari, E. Vertua, L. Gibelli, G. S. Wengler, and O. Parolini Human Amnion Mesenchyme Harbors Cells with Allogeneic T-Cell Suppression and Stimulation Capabilities Stem Cells, January 1, 2008; 26(1): 182 - 192. [Abstract] [Full Text] [PDF]

				Z. Selmani, A. Naji, I. Zidi, B. Favier, E. Gaiffe, L. Obert, C. Borg, P. Saas, P. Tiberghien, N. Rouas-Freiss, et al. Human Leukocyte Antigen-G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4+CD25highFOXP3+ Regulatory T Cells Stem Cells, January 1, 2008; 26(1): 212 - 222. [Abstract] [Full Text] [PDF]

				A. J. Nauta and W. E. Fibbe Immunomodulatory properties of mesenchymal stromal cells Blood, November 15, 2007; 110(10): 3499 - 3506. [Abstract] [Full Text] [PDF]

				I. Rasmusson, M. Uhlin, K. Le Blanc, and V. Levitsky Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes J. Leukoc. Biol., October 1, 2007; 82(4): 887 - 893. [Abstract] [Full Text] [PDF]

				N. Gupta, X. Su, B. Popov, J. W. Lee, V. Serikov, and M. A. Matthay Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice J. Immunol., August 1, 2007; 179(3): 1855 - 1863. [Abstract] [Full Text] [PDF]

				F. Locatelli, R. Maccario, and F. Frassoni Mesenchymal stromal cells, from indifferent spectators to principal actors. Are we going to witness a revolution in the scenario of allograft and immune-mediated disorders? Haematologica, July 1, 2007; 92(7): 872 - 877. [Full Text] [PDF]

				C. Prevosto, M. Zancolli, P. Canevali, M. R. Zocchi, and A. Poggi Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction Haematologica, July 1, 2007; 92(7): 881 - 888. [Abstract] [Full Text] [PDF]

				X. Chen, A. McClurg, G.-Q. Zhou, M. McCaigue, M. A. Armstrong, and G. Li Chondrogenic Differentiation Alters the Immunosuppressive Property of Bone Marrow-Derived Mesenchymal Stem Cells, and the Effect Is Partially due to the Upregulated Expression of B7 Molecules Stem Cells, February 1, 2007; 25(2): 364 - 370. [Abstract] [Full Text] [PDF]

				C.-J. Chang, M.-L. Yen, Y.-C. Chen, C.-C. Chien, H.-I. Huang, C.-H. Bai, and B. L. Yen Placenta-Derived Multipotent Cells Exhibit Immunosuppressive Properties That Are Enhanced in the Presence of Interferon-{gamma} Stem Cells, November 1, 2006; 24(11): 2466 - 2477. [Abstract] [Full Text] [PDF]

				J. M. van Laar and A. Tyndall Adult stem cells in the treatment of autoimmune diseases Rheumatology, October 1, 2006; 45(10): 1187 - 1193. [Abstract] [Full Text] [PDF]

				J. J. Minguell and A. Erices Mesenchymal Stem Cells and the Treatment of Cardiac Disease Experimental Biology and Medicine, January 1, 2006; 231(1): 39 - 49. [Abstract] [Full Text] [PDF]