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 B (NF-kB) 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. STEM CELLS 2008;26:279–289

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 / F. LIOTTA; R. ANGELI; L. COSMI; L. FILI; C. MANUELLI; F. FROSALI; B. MAZZINGHI; L. MAGGI; A. PASINI; V. LISI; V. SANTARLASCI; L. CONSOLONI; M.L. ANGELOTTI; P. ROMAGNANI; P. PARRONCHI; M. KRAMPERA; E. MAGGI; S. ROMAGNANI; F. ANNUNZIATO. - In: STEM CELLS. - ISSN 1066-5099. - STAMPA. - 26:(2008), pp. 279-289. [10.1634/stemcells.2007-0454]

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

LIOTTA, FRANCESCO;ANGELI, ROBERTA;COSMI, LORENZO;FILI', LUCIA;MANUELLI, CINZIA;FROSALI, FRANCESCA;MAZZINGHI, BENEDETTA;MAGGI, LAURA;SANTARLASCI, VERONICA;ROMAGNANI, PAOLA;PARRONCHI, PAOLA;MAGGI, ENRICO;ROMAGNANI, SERGIO;ANNUNZIATO, FRANCESCO
2008

Abstract

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 B (NF-kB) 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. STEM CELLS 2008;26:279–289
2008
26
279
289
F. LIOTTA; R. ANGELI; L. COSMI; L. FILI; C. MANUELLI; F. FROSALI; B. MAZZINGHI; L. MAGGI; A. PASINI; V. LISI; V. SANTARLASCI; L. CONSOLONI; M.L. ANGELOTTI; P. ROMAGNANI; P. PARRONCHI; M. KRAMPERA; E. MAGGI; S. ROMAGNANI; F. ANNUNZIATO
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/254850
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