Immunomodulation by mesenchymal stem cells: Interplay between mesenchymal stem cells and regulatory lymphocytes

Figure 1 Immunosuppression by mesenchymal stem cells. MSCs suppress innate and adaptive immune responses by enhancing regulatory immune cells with tolerogenic properties. MSCs suppress macrophages by favoring monocyte polarization to anti-inflammatory M2 macrophages, increasing the production of IL-10, and decreasing the production TNF-α and IL-12. MSCs can also regulate DCs by downregulating the expression of MHC, CD40, CD80, CD83 and CD86, thus, diminishing their antigen presenting ability, while upregulating the expression of IL-10. MSCs can reduce the NK cell cytotoxicity and decrease their production of TNF-α and IFN-γ. T_reg and B_reg cells can be induced by MSCs, further increase the production of anti-inflammatory cytokines (IL-10 and TGF-β1). However, the mechanisms of how B_reg cells are induced by MSCs are still not clear. MSCs: Mesenchymal stem cells; TNF: Tumor necrosis factor; IL: Interleukin; NK: Natural killer; DCs: Dendritic cells; IFN-γ: Interferon-γ; T_reg: Regulatory T; B_reg: Regulatory B; TGF: Transforming growth factor; PGE2: Prostaglandin E2; IDO: Indoleamine 2,3-dioxygenase.

Figure 2 Mesenchymal stem cells-mediated regulatory T cell induction. MSCs induce T_reg cells through soluble mediators stimulation, cell-cell interaction, and modulation of antigen-presenting cells. Under inflammatory environment, MSCs secretes TGF-β1, PGE2 and IDO to facilitate the differentiation of naïve T cells to Foxp3⁺T_reg cells. MSCs can also interact with Th17 cells by direct contact via CD54 and C11a/CD18. With the presence of PGE2, differentiated Th17 cells can be converted to functional Foxp3⁺T_reg cells. MSCs can increase the secretion of IL-10 by antigen presenting cells, which will then induce Tr1 cells differentiation. MSCs: Mesenchymal stem cells; IL: Interleukin; T_reg: Regulatory T; TGF: Transforming growth factor; PGE2: Prostaglandin E2; IDO: Indoleamine 2,3-dioxygenase.