Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD41 T cells toward the Th17 phenotype was examined. CD4 1 T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naïve-and memoryphenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cellcontact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.Key words: Immunosuppression . Mesenchymal stem cells . Stem cells . T helper cells . Th17 cells Supporting Information available online IntroductionThe immune suppressive properties of mesenchymal stem cells (MSCs) have garnered increasing attention over the past decade and constitute a central mechanism for MSC therapeutic benefits [1][2][3][4]. Specific modulatory effects of MSCs from human and experimental animal sources have been described for the differentiation, activation, proliferation and effector functions of multiple innate and adaptive immune cells [5][6][7][8][9][10][11]. Among these, MSC-mediated inhibition of primary T-cell activation and proliferation, suppression of DC maturation and promotion of regulatory phenotypes in 2840monocyte/macrophages and T cells have been most extensively characterised [7-9, 11, 12].In keeping with a paracrine or ''trophic'' model of MSC function in vivo [13], various MSC-produced soluble mediators have been implicated in these immunomodulatory effects including IL-10, IL-6, HGF, TGF-b, chemokine ligand-2 (CCL2), HLA-G, NO, tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2 (PGE2) and kyneurenine [1,2,7,9,12,[14][15][16]. For some such mediators, expression by MSCs may be dependent on pre-exposure to exogenous factors (e.g. IFN-g, TNF) or on contact-dependent MSC/target cell cross-talk [2,7,[16][17][18][19]. The potential for harnessing MSC immunomodulatory properties has been highlighted by results in pre-clinical models of autoimmunity, allotransplantation, sepsis and acu...

The absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC. (Hepatology 2017).

A mutual interplay exists between adaptive immune system and gut microbiota. Altered gut microbial ecosystems are associated with the metabolic syndrome, occurring in most obese individuals. However, it is unknown why 10–25% of obese individuals are metabolically healthy, while normal weight individuals can develop inflammation and atherosclerosis. We modeled these specific metabolic conditions in mice fed with a chow diet, an obesogenic but not inflammatory diet—mimicking healthy obesity, or Paigen diet—mimicking inflammation in the lean subjects. We analyzed a range of markers and cytokines in the aorta, heart, abdominal fat, liver and spleen, and metagenomics analyses were performed on stool samples. T lymphocytes infiltration was found in the aorta and in the liver upon both diets, however a significant increase in CD4+ and CD8+ cells was found only in the heart of Paigen-fed animals, paralleled by increased expression of IL-1, IL-4, IL-6, IL-17, and IFN-γ. Bacteroidia, Deltaproteobacteria, and Verrucomicrobia dominated in mice fed Paigen diet, while Gammaproteobacteria, Delataproteobacteria, and Erysipelotrichia were more abundant in obese mice. Mice reproducing human metabolic exceptions displayed gut microbiota phylogenetically distinct from normal diet-fed mice, and correlated with specific adaptive immune responses. Diet composition thus has a pervasive role in co-regulating adaptive immunity and the diversity of microbiota.