Toll-like Receptors 3 and 4 Are Expressed by Human Bone Marrow-Derived Mesenchymal Stem Cells and Can Inhibit Their T-cell Modulatory Activity by Impairing Notch Signaling

Stem Cells. 2008 Jan;26(1):279-89. doi: 10.1634/stemcells.2007-0454. Epub 2007 Oct 25.

Abstract

Bone marrow (BM)-derived mesenchymal stem cells (MSCs) are multipotent, nonhemopoietic progenitors that also possess regulatory activity on immune effector cells through different mechanisms. We demonstrate that human BM-derived MSCs expressed high levels of Toll-like receptors (TLRs) 3 and 4, which are both functional, as shown by the ability of their ligands to induce nuclear factor kappaB (NF-kappaB) activity, as well as the production of interleukin (IL)-6, IL-8, and CXCL10. Of note, ligation of TLR3 and TLR4 on MSCs also inhibited the ability of these cells to suppress the proliferation of T cells, without influencing their immunophenotype or differentiation potential. The TLR triggering effects appeared to be related to the impairment of MSC signaling to Notch receptors in T cells. Indeed, MSCs expressed the Notch ligand Jagged-1, and TLR3 or TLR4 ligation resulted in its strong downregulation. Moreover, anti-Jagged-1 neutralizing antibody and N[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of Notch signaling, hampered the suppressive activity of MSCs on T-cell proliferation. These data suggest that TLR3 and TLR4 expression on MSCs may provide an effective mechanism to block the immunosuppressive activity of MSCs and therefore to restore an efficient T-cell response in the course of dangerous infections, such as those sustained by double-stranded RNA viruses or Gram-negative bacteria, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Chemokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation / immunology
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Microscopy, Confocal
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Receptors, Notch / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Toll-Like Receptor 3 / metabolism*
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Chemokines
  • Receptors, Notch
  • TLR3 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4