Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into mesenchymal lineages and that can be isolated from various tissues and easily cultivated in vitro. Currently, MSCs are of considerable interest because of the biological characteristics that confer high potential applicability in the clinical treatment of many diseases. Specifically, because of their high immunoregulatory capacity, MSCs are used as tools in cellular therapies for clinical protocols involving immune system alterations. In this review, we discuss the current knowledge about the capacity of MSCs for the immunoregulation of immunocompetent cells and emphasize the effects of MSCs on T cells, principal effectors of the immune response, and the immunosuppressive effects mediated by the secretion of soluble factors and membrane molecules. We also describe the mechanisms of MSC immunoregulatory modulation and the participation of MSCs as immune response regulators in several autoimmune diseases, and we emphasize the clinical application in graft versus host disease (GVHD).

Figure 1

Immunoregulatory effect of MSCs on T lymphocytes. MSCs can induce the sustained expression of CTLA-4 and CD69 activation molecules on T cells, which have been related with generation of cells with immunoregulatory properties. Cell-to-cell contact seems to be required for the increase of CTLA-4 expression. Dependent and independent mechanisms of cellular contact are involved in the decrease of proliferation of CD4⁺ and CD8⁺ T cells and in generation of Foxp3⁺ Tregs by MSCs. Cytokines such as IL-10 can stimulate the expression and secretion of HLA-G5 by MSCs and in turn it stimulates the secretion of IL-10 in a positive feedback loop. The initial contact between MSCs and T lymphocytes seems to be required for initiation of the feedback loop. PGE₂ secreted by MSCs is involved in generation of Tr1 cells. HLA-G5 supports differentiation of Th2 cells and IDO decrease differentiation of Th17.

Figure 2

Immunoregulatory effects of MSCs on immune cells. Proinflammatory cytokines such as IFNγ secreted by activated NK cells and T lymphocytes support MSCs-mediated immunoregulation and can increase or induce the production of immunosuppressive molecules. IDO, PGE₂, TGF_β1, and membrane molecules are mainly involved in MSCs immunoregulation on NK cells. IDO, PGE₂, and IL-10 are involved in the decrease of differentiation of monocytes into iDCs and may push mDCs toward an immature state, which results in T-cell anergy and inappropriate activation of T lymphocytes. MSCs induce the differentiation of CD34⁺ hematopoietic progenitors into a population of regulatory DCs, which in turn stimulate the generation of Foxp3⁺ Tregs.