Abstract
Mesenchymal stromal cells (MSC) control excessive inflammation and create a microenvironment for tissue repair protecting from chronic inflammation and tissue fibrosis. We examined the molecular mechanisms of MSC immunomodulatory function in mixed cultures of human adipose-derived MSC with lymphocytes. Our data show that MSC promote unstimulated lymphocyte survival potentially by an increase in antigen presentation. Under inflammatory conditions, mimicked by stimulation of TCR in lymphocytes, MSC suppress activation and proliferation of stimulated T cells. Immunosuppression is accompanied by downregulation of IL-2Rα that negatively affects the survival of activated T cells. MSC upregulate transcription of indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS), which generate products negatively affecting T cell function. Both MSC and lymphocytes dramatically increase the surface ICAM-1 level in mixed cultures. Antibody-mediated blockage of surface ICAM-1 partially releases MSC-mediated immune suppression in vitro. Our data suggest that MSC have cell-intrinsic molecular programs depending on the inflammatory microenvironment. We speculate that MSC sense soluble factors and respond by surface ICAM-1 upregulation. ICAM-1 is involved in the control of T cell activation leading to immunosuppression or modest stimulation depending on the T cell status. Immunomodulation by MSC ranging from support of naive T cell survival to immunosuppression of activated T cells may affect the tissue microenvironment protecting from aberrant regeneration.
Highlights
Mesenchymal stromal cells (MSC) were discovered as fibroblast-like cells from the bone marrow [1]
It has been shown that proinflammatory cytokines trigger receptors on the surface of MSC leading to activation of genes and increase in a level of the so-called effector molecules, such as IDO and inducible nitric oxide (NO) synthase (iNOS), and secretion of immune suppressive cytokines, in particular, transforming growth factor beta (TGF-β) and IL-10 [20, 33]
Despite understanding of the “big picture”, a significant controversy concerning the difference in molecular mechanisms between cell contact-independent paracrine and cell contact-dependent immune suppression exists [36]
Summary
Mesenchymal stromal cells (MSC) were discovered as fibroblast-like cells from the bone marrow [1]. Activated lymphocytes in vitro secrete soluble factors, such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) that initiate the MSC immunosuppression program, which induces synthesis of protein factors, in particular, indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS) [10, 11] Products of their enzymatic activity (kynurenine and NO) suppress lymphocyte function and proliferation. The list of candidate molecules involved in contact mechanisms of immunosuppression was narrowed down to programmed death-1 receptor/programmed death-1 receptor ligand (PD-1/PD-L1) [22], the B7 family immuneregulatory orphan ligand H4 (В7-Н4) [23], intercellular adhesion molecules of adhesion molecule family (ICAM), and vascular cell adhesion molecule (VCAM) [24] As it was mentioned above, MSC can affect the activity of immune cells and regulate an arresting of inflammatory response [25]. It is likely that ICAM-1 serves as molecular switch responsible for activation of the immune suppressive program in hASC
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