TLR3 and 4 Ligation Abrogates Mesenchymal Stem Cell Immune Suppression

Florence, Italy -

Mesenchymal stem cells are known to suppress immune responses in antigen specific and non-specific ways.

In a recent paper (Liotta et al. 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. Stem Cells. 2007 Oct 25) it was demonstrated that human bone marrow mesenchymal stem cells express the "danger receptors" toll like receptor 3 (which binds double stranded RNA) and toll like receptor 4 (which binds LPS and innate self antigens). Activating these receptors blocked ability of mesenchymal stem cells to inhibit T cell responses through downregulating expression of Jagged-1 on the mesenchymal stem cells. Jagged-1 is a ligand for notch.

The methods by which a mesenchymal stem cell decides to stimulate or inhibit T cell activity are not understood. On the one hand it would be logical that inflammatory stimuli would activity immune suppressive molecules from mesenchymal stem cells in order to provide feedback inhibition. This does not seem to be the case here, since immune stimulatory molecules, such as TLR3 and 4 agonists actually take away the immune suppressive activities of the mesenchymal stem cell.

The role of Jagged-1 on mesenchymal stem cells is also very interesting. There is at least one publication (Li et al. Jagged1 protein enhances the differentiation of mesenchymal stem cells into cardiomyocytes. Biochem Biophys Res Commun. 2006 Mar 10;341(2):320-5) showing that the Jagged-1 interaction with notch is involved in differentiation of mesenchymal stem cells to cardiomyocytes. The possible involvement of immune response in terms of shifting cellular differentiation programs is a very interesting area for future study.