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.

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 Jagged-1/Notch pathway / Liotta F; Angeli R; Cosmi L; Filì L; Manuelli C; Frosali F; Mazzinghi B; Maggi L; Pasini A; Santarlasci V; Angelotti ML; Romagnani P; Parronchi P; Maggi E; Romagnani S; Annunziato F. - STAMPA. - (2008), pp. 69-70. (Intervento presentato al convegno 6th National Conference of Italian Society of Immunology, Clinical Immunology and Allergology tenutosi a Roma, Italy nel June 11-14 2008).

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 Jagged-1/Notch pathway

Liotta F;Cosmi L;Filì L;Manuelli C;Frosali F;Maggi L;Santarlasci V;Angelotti ML;Romagnani P;Parronchi P;Maggi E;Annunziato F
2008

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.
2008
Stem Cells. 2008 Jan;26(1):279-89. Epub 2007 Oct 25.
6th National Conference of Italian Society of Immunology, Clinical Immunology and Allergology
Roma, Italy
June 11-14 2008
Liotta F; Angeli R; Cosmi L; Filì L; Manuelli C; Frosali F; Mazzinghi B; Maggi L; Pasini A; Santarlasci V; Angelotti ML; Romagnani P; Parronchi P; Maggi E; Romagnani S; Annunziato F
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/428514
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