Human monocyte-derived suppressor cells control graft-versus-host disease by inducing regulatory forkhead box protein 3-positive CD8+ T lymphocytes

J Allergy Clin Immunol. 2015 Jun;135(6):1614-24.e4. doi: 10.1016/j.jaci.2014.12.1868. Epub 2015 Jan 25.

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.

Conclusion: 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.

Keywords: Human monocyte-derived suppressor cells; T lymphocytes; graft-versus-host disease; inflammation; regulatory T cells; signal transducer and activator of transcription 3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Differentiation / drug effects
  • Cell Proliferation
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression Regulation
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / prevention & control*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Immunosuppression
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin-6 / pharmacology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / transplantation
  • Primary Cell Culture
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Transplantation, Heterologous

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL6 protein, human
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Granulocyte-Macrophage Colony-Stimulating Factor