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TRANSLATIONAL AND CLINICAL RESEARCH

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

^aExcellence Center of the University of Florence De Novo Therapy, Florence, Italy;
^bSection of Haematology, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy

Key Words. Tolerance • Suppression • Anergy • Stem cells • T cells • Notch

Correspondence: Correspondence: Sergio Romagnani, Ph.D., Department of Internal Medicine, University of Florence, Viale Morgagni 85, Firenze 50134, Italy. Telephone: 39-055-413663; Fax: 39-055-4271500; e-mail: s.romagnani{at}dmi.unifi.it

Received on June 15, 2007; accepted for publication on October 15, 2007.

First published online in STEM CELLS EXPRESS  October 25, 2007.


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 B (NF-B) 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.

Disclosure of potential conflicts of interest is found at the end of this article.

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