title: Smad3-deficient CD11b(+)Gr1(+) myeloid-derived suppressor cells prevent allograft rejection via the nitric oxide pathway.
abstract: Immunosuppressive CD11b(+)Gr1(+) myeloid-derived suppressor cells and TGF-β have been shown to negatively regulate host immunity against allografts. Our results demonstrated that Smad3-deficient mice or mice reconstituted with Smad3-deficient hematopoietic cells rejected allogeneic skin or heart grafts in a significantly slower manner compared with littermates or wild-type (WT) control mice. Transplanted Smad3(-/-) recipients produced markedly less anti-donor IgG Abs, especially IgG1 and IgG2b subclasses. T cells in alloskin-grafted Smad3-deficient mice were more likely to participate in a Th2-type immune response, as evidenced by more Th2-specific transcription factor, GATA3 expression, and increased IL-4 and IL-10 production, as well as less Th1-specific transcription factor, T-bet expression, and decreased IL-2 and IFN-γ production. More CD11b(+)Gr1(+) neutrophil infiltration and less monocyte/macrophage and T cell infiltration in allografts were observed in Smad3(-/-) recipients compared with WT recipients. Increased CXCL1 and CXCL2 as well as decreased CCL3, MCP-1, and RANTES chemokines in allografts of Smad3(-/-) recipients were consistently detected by real-time PCR. Further studies indicated that the increased CD11b(+)Gr1(+) myeloid cells in Smad3-deficient mice were immunosuppressive and responsible for the delayed allograft rejection mainly via an NO-dependent pathway. Thus, this study identifies Smad3 as an intrinsic negative regulator that critically inhibits the differentiation and function of immunosuppressive CD11b(+)Gr1(+) myeloid-derived suppressor cells.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.forename: Chenming
authors.initials: C
authors.lastname: Sun
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhen
authors.forename: Jianxia
authors.initials: J
authors.lastname: Peng
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D039481:CD11b Antigen; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007518:Isoantibodies / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D051900:Smad3 Protein; D018418:Th2 Cells / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D039481:CD11b Antigen; D018925:Chemokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007074:Immunoglobulin G; D007518:Isoantibodies; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D009569:Nitric Oxide