Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells
Tóm tắt
The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell–receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor–β–neutralizing antibody had no effect. Finally, MSCs from inducible NOS−/− mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.
Tài liệu tham khảo
Meirelles Lda S and Nardi NB. Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Br J Haematol2003; 123:702–711.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science1999; 284:143–147.
Kawada H, Fujita J, Kinjo K, et al. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood2004; 104:3581–3587.
Koc ON, Gerson SL, Cooper BW, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol2000; 18:307–316.
Noort WA, Kruisselbrink AB, in't Anker PS, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol2002; 30:870–878.
in't Anker PS, Noort WA, Kruisselbrink AB, et al. Nonexpanded primary lung and bone marrow-derived mesenchymal cells promote the engraftment of umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol2003; 31:881–889.
Koc ON, Peters C, Aubourg P, et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol1999; 27:1675–1681.
Bensidhoum M, Chapel A, Francois S, et al. Homing of in vitro expanded Stro-1− or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment. Blood2004; 103:3313–3319.
Maitra B, Szekely E, Gjini K, et al. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant2004; 33:597–604.
Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood2005; 105:2214–2219.
Groh ME, Maitra B, Szekely E, et al. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol2005; 33:928–934.
Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood2003; 101:3722–3729.
Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood2002; 99:3838–3843.
Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood2004; 103:4619–4621.
Aggarwal S and Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood2005; 105:1815–1822.
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation2003; 75:389–397.
Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood2003; 102:3837–3844.
Mazzoni A, Bronte V, Visintin A, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol2002; 168:689–695.
Bingisser RM, Tilbrook PA, Holt PG, Kees UR. Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J Immunol1998; 160:5729–5734.
Albina JE, Abate JA, Henry WL Jr. Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation: role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol1991; 147:144–148.
Young MR, Wright MA, Matthews JP, Malik I, Prechel M. Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-beta and nitric oxide. J Immunol1996; 156:1916–1922.
Medot-Pirenne M, Heilman MJ, Saxena M, McDermott PE, Mills CD. Augmentation of an antitumor CTL response in vivo by inhibition of suppressor macrophage nitric oxide. J Immunol1999; 163:5877–5882.
Lejeune P, Lagadec P, Onier N, Pinard D, Ohshima H, Jeannin JF. Nitric oxide involvement in tumor-induced immunosuppression. J Immunol1994; 152:5077–5083.
Angulo I, de las Heras FG, Garcia-Bustos JF, Gargallo D, Munoz-Fernandez MA, Fresno M. Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood2000; 95:212–220.
Bobe P, Benihoud K, Grandjon D, Opolon P, Pritchard LL, Huchet R. Nitric oxide mediation of active immunosuppression associated with graft-versus-host reaction. Blood1999; 94:1028–1037.
Mais A, Klein T, Ullrich V, Schudt C, Lauer G. Prostanoid pattern and iNOS expression during chondrogenic differentiation of human mesenchymal stem cells. J Cell Biochem2005; 94:307–316.
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood2005; 105:2821–2827.
Moriggl R, Topham DJ, Teglund S, et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity1999; 10:249–259.
Bogdan C. Nitric oxide and the immune response. Nat Immunol2001; 2:907–916.
Stolz DB, Zamora R, Vodovotz Y, et al. Peroxisomal localization of inducible nitric oxide synthase in hepatocytes. Hepatology2002; 36:81–93.
Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science2005; 310:1966–1970.
Clancy R, Varenika B, Huang W, et al. Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J Immunol2000; 165:1582–1587.