1. 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
- Author
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Annalisa Pasini, Francesca Frosali, Veronica Lisi, Lucia Filì, Sergio Romagnani, Cinzia Manuelli, Maria Lucia Angelotti, Lara Consoloni, Roberta Angeli, Benedetta Mazzinghi, Laura Maggi, Paola Romagnani, Veronica Santarlasci, Francesco Liotta, Francesco Annunziato, Paola Parronchi, Lorenzo Cosmi, Mauro Krampera, and Enrico Maggi
- Subjects
CD4-Positive T-Lymphocytes ,Chemokine ,Cellular differentiation ,T cell ,Notch signaling pathway ,T cells ,Bone Marrow Cells ,Enzyme-Linked Immunosorbent Assay ,Lymphocyte Activation ,anergy ,stem cells ,tolerance, suppression, anergy, stem cells, T cells, notch ,medicine ,Humans ,Cells, Cultured ,Cell Proliferation ,Microscopy, Confocal ,tolerance ,Receptors, Notch ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Multipotent Stem Cells ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,suppression ,Flow Cytometry ,Toll-Like Receptor 3 ,Cell biology ,Toll-Like Receptor 4 ,medicine.anatomical_structure ,Multipotent Stem Cell ,biology.protein ,Molecular Medicine ,Bone marrow ,Chemokines ,Stem cell ,Signal Transduction ,Developmental Biology ,notch - 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 κB (NF-κB) 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.
- Published
- 2008