title: Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis.
abstract: Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)-dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL(-/-) BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL-mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGFβ, which in turn led to the upregulation of CD4(+)CD25(+)Foxp3(+) regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis.
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: DanDan
authors.initials: D
authors.lastname: Wang
authors.forename: Xingtian
authors.initials: X
authors.lastname: Xu
authors.forename: Cunye
authors.initials: C
authors.lastname: Qu
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaza
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.forename: WanJun
authors.initials: W
authors.lastname: Chen
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D016264:Dextran Sulfate / Q000008:administration & dosage; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*; D054392:Adipokines
chemical_list: D018932:Chemokine CCL2; D016264:Dextran Sulfate; D053222:Fas Ligand Protein; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D019014:fas Receptor; C491768:Ccl2 protein, mouse; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse