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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
- Publication Year :
- 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 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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....d49d3a2ad7f7cc145536b557f3522bd3