Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype

Abstract

Mesenchymal stem cells (MSCs) exert immunomodulatory properties via the inhibition of T cell activation and proliferation. Because of the deleterious role of Th17 cells in the pathogenesis of inflammatory disease, we investigated whether proinflammatory cytokines could modify the expression of adhesion molecules on human MSCs, thereby contributing to increased Th17 cell adhesion to MSCs and, as a consequence, modulating the function of the latter cells. IFN-γ and TNF-α synergistically enhanced the expression of CD54 by MSCs, enabling the CCR6 chemokine ligand CCL20 to induce in vitro adhesion of Th17 cells to MSCs. MSCs prevented the in vitro differentiation of naive CD4+ T cells into Th17 cells and inhibited the production of IL-17, IL-22, IFN-γ, and TNF-α by fully differentiated Th17 cells; this was mediated, in part, via PGE2, the production of which was enhanced in cocultures with Th17 cells. Moreover, MSCs induced the production of IL-10 and trimethylation of histone H3K4me3 at the promoter of the FOXP3 gene locus, whereas it suppressed trimethylation of the corresponding region in the RORC gene in Th17 cells. These epigenetic changes were associated with the induction of fork head box p3 and the acquisition by Th17 cells of the capacity to inhibit in vitro proliferative responses of activated CD4+ T cells, which was enhanced when MSCs were preincubated with IFN-γ and TNF-α. These results showed that, under inflammatory conditions, MSCs mediate the adhesion of Th17 cells via CCR6 and exert anti-inflammatory effects through the induction of a T cell regulatory phenotype in these cells.

Allogeneic mesenchymal stem cells: Agents of immune modulation

“…Indeed some studies suggest that there is a requirement for IFN-g, and/or IL-1b in the activation of MSC immune suppressive functions [Ren et al, 2008], a finding that parallels repair in non-mammalian systems where inflammation is a prerequisite for regeneration [Young, 2004]. The differentiation of CD4 þ T cells to specific subsets is also influenced by MSC; with the mesenchymal cell skewing T cell responses towards regulatory patterns of cytokine secretion and concurrent suppression of Th1, Th2 or Th17 responses [Nemeth et al, 2009;Rafei et al, 2009;Ghannam et al, 2010]. These data are supported by elegant in vivo models of transplantation and autoimmune disease where MSC alter T cell polarisation away from the typical effector responses [Casiraghi et al, 2008;Ge et al, 2009;Rafei et al, 2009;Kavanagh and Mahon, 2011].…”

Preserved β-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells

“…MSCs also have unique immunomodulatory capacities (6). They can suppress T-cell proliferation in response to nominal antigens or alloantigens (7) and upregulate the number of regulatory T cells (8,9). MSCmediated immunosuppression is also associated with a reduction in inflammatory cytokine production (10).…”

Mesenchymal stem cells differentially mediate regulatory T cells and conventional effector T cells to protect fully allogeneic islet grafts in mice

“…The steadily growing interest in MSC-mediated immunosuppression has involved its potential in the activation, expansion and induction of T reg cells from conventional CD4 + T eff cells both in vivo and in vitro [29][30][31]. We previously demonstrated that matrix metalloproteinases -2 and -9 secreted by MSCs play an important role in MSC- Fig.…”