title: Human monocyte-derived suppressor cells control graft-versus-host disease by inducing regulatory forkhead box protein 3-positive CD8+ T lymphocytes.
abstract: BACKGROUND
  Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells.
  
  
  OBJECTIVE
  We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders.
  
  
  METHODS
  HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice).
  
  
  RESULTS
  CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice.
  
  
  CONCLUSIONS
  Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France. Electronic address: Nona.Janikashvili@u-bourgogne.fr.
authors: Nona
authors: N
authors: Janikashvili
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Malika
authors: M
authors: Trad
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Alexandrine
authors: A
authors: Gautheron
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Internal Medicine, University Hospital, Dijon, France.
authors: Maxime
authors: M
authors: Samson
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Baptiste
authors: B
authors: Lamarthée
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Francis
authors: F
authors: Bonnefoy
authors: INSERM UMR866, University of Bourgogne, Dijon, France.
authors: Stéphanie
authors: S
authors: Lemaire-Ewing
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Marion
authors: M
authors: Ciudad
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Khatuna
authors: K
authors: Rekhviashvili
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Famky
authors: F
authors: Seaphanh
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Béatrice
authors: B
authors: Gaugler
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France.
authors: Sylvain
authors: S
authors: Perruche
authors: Cancer Sciences, University of Southampton, Southampton, United Kingdom.
authors: Andrew
authors: A
authors: Bateman
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Pathology and Cytology, University Hospital, Dijon, France.
authors: Laurent
authors: L
authors: Martin
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Internal Medicine, University Hospital, Dijon, France.
authors: Sylvain
authors: S
authors: Audia
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; CHU Besançon, CIC-BT506, FHU INCREASE, Besançon, France.
authors: Philippe
authors: P
authors: Saas
authors: Department of Pediatrics, Steele Children's Research Center, Department of Immunobiology, BIO5 Institute and Arizona Cancer Center, University of Arizona, Tucson, Ariz.
authors: Nicolas
authors: N
authors: Larmonier
authors: INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Internal Medicine, University Hospital, Dijon, France.
authors: Bernard
authors: B
authors: Bonnotte
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007165:Immunosuppression Therapy; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D061251:Primary Cell Culture; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508600:IL6 protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Human monocyte-derived suppressor cells; T lymphocytes; graft-versus-host disease; inflammation; regulatory T cells; signal transducer and activator of transcription 3