TLR3 and TLR4 are Expressed by Human Bone Marrow-Derived Mesenchymal Stem Cells And Can Inhibit Their T-cell Modulatory Activity by Impairing Notch Signalling

¹ The Excellence Center of the University of Florence DENOTHE, Florence, Italy
² The Excellence Center of the University of Florence DENOTHE, Florence, Italy. The Department of Clinical and Experimental Medicine, Section of Haematology, University of Verona, Verona

^* To whom correspondence should be addressed. E-mail: s.romagnani{at}dmi.unifi.it.

	Abstract

Bone marrow (BM)-derived mesenchymal stem cells (MSCs) are multipotent, non hemopoietic progenitors which 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 NF-B activity, as well as the production of 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 TLRs triggering effects appeared to be related to the impairment of MSCs signaling to Notch receptors in T cells. Indeed, MSCs expressed the Notch ligand Jagged-1 and TLR3 or TLR4 ligation resulted in its strong down-regulation. Moreover, anti-Jagged-1 neutralizing antibody and N[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester, an inhibitor of Notch signalling, hampered the suppressive activity of MSCs on T-cell proliferation.