title: 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.
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.
authors.affiliation: Excellence Center of the University of Florence De Novo Therapy, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Liotta
authors.forename: Roberta
authors.initials: R
authors.lastname: Angeli
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Lucia
authors.initials: L
authors.lastname: Filì
authors.forename: Cinzia
authors.initials: C
authors.lastname: Manuelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Frosali
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pasini
authors.forename: Veronica
authors.initials: V
authors.lastname: Lisi
authors.forename: Veronica
authors.initials: V
authors.lastname: Santarlasci
authors.forename: Lara
authors.initials: L
authors.lastname: Consoloni
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Angelotti
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.forename: Paola
authors.initials: P
authors.lastname: Parronchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Krampera
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D018613:Microscopy, Confocal; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D051880:Receptors, Notch; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4