Human mesenchymal stromal cells modulate T-cell responses through TNF-α-mediated activation of NF-κB

Eur J Immunol. 2014 Feb;44(2):480-8. doi: 10.1002/eji.201343668. Epub 2013 Dec 4.

Abstract

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR stimulation of T cells. Inhibition of NF-κB through silencing of IκB kinase β or the TNF-α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC-associated NF-κB activation primarily leads to inhibition of T-cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF-α/NF-κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF-κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.

Keywords: Immunoregulation; MSC; NF-κB; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Humans
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation / immunology*
  • Mesenchymal Stem Cells / immunology*
  • Mesenchymal Stem Cells / metabolism*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Lectins, C-Type
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase