Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Figure 6 Effects of cytokine milieu on mesenchymal stem cell immune-modulation. Mesenchymal stem cell (MSC) modulation of immune responses is strongly affected by the makeup of cytokine milieus. Toll-like receptor (TLR) ligation in conjunction with interferon signaling drives MSCs down a pro-inflammatory route. While high concentrations of the pro-inflammatory cytokines IFNγ and either tumor necrosis factor-α (TNF-α) or IL-1 have been shown to induce iNOS and NO in MSCs to mediate suppression of T cell proliferation, low concentrations of these factors fail to fully induce iNOS, and instead enhance T cell proliferation, presumably via cytokine-induced chemokines. Furthermore, MSCs differentially affect the polarization of effector CD8+ T cell subsets: through enhanced early IL-2 expression induced by MSCs, activated CD8+ T cells exhibit increased IFNγ expression and cytotoxicity, while fully differentiated cytotoxic T lymphocytes (CTLs) are largely unaffected by MSC action. In contrast, MSCs potently suppress Tc17 development. Moreover, IL-6 signaling acts as a switch for MSC immune-modulation of macrophages. In the presence of IL-6, MSCs retain promotion of M2, but favor M1 polarization in the absence of this cytokine.