Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update

Abstract

Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4⁺ T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8⁺ T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.

Keywords: T cells; dendritic cells; immunomodulation; macrophages; mesenchymal stromal cells.

FIGURE 1

MSCs alter the phenotype and function of monocytes/macrophages, DCs, T- and B-cells. Soluble molecules and EVs released by MSCs induce a shift toward an M2 phenotype, which is accompanied by a reduced secretion of proinflammatory cytokines and an increased production of anti-inflammatory molecules. Furthermore, the expression of CD86 and MHC II as well as their phagocytic and antigen presentation capacity is impaired by MSCs. Additionally, MSCs inhibit the maturation and differentiation of DCs, resulting in a reduced expression of costimulatory molecules, increase the expression of PD-L1, and shift their cytokine profile from proinflammatory toward regulatory. This interaction is mediated by cell-membrane-associated and soluble molecules. MSCs impair both CD4⁺ and CD8⁺ T cells via soluble factors, mitochondrial transfer, and EVs. They also inhibit the generation of Th1 and Th17 cells, while promoting Tregs and Th2 cells. Moreover, they decrease the cytokine secretion and cytotoxicity of CTLs. Furthermore, MSCs hinder the proliferation, maturation, and antibody secretion of B cells and foster the generation of IL-10-producing Bregs.