Specific GSK126 cell line 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 5–11. Among these, MSC-mediated inhibition of primary T-cell activation and proliferation, suppression of DC maturation and promotion of regulatory phenotypes in monocyte/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-β, 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, 14–16. For some such mediators, expression by MSCs may be dependent on pre-exposure to exogenous factors (e.g. IFN-γ, TNF) or on contact-dependent MSC/target cell cross-talk 2, 7, 16–19. The potential for harnessing MSC immunomodulatory

properties has been highlighted by results in pre-clinical models of autoimmunity, allotransplantation, sepsis and acute ischemic injury 1, 4, 7, 14, 15 as well as by outcomes from clinical trials in inflammatory bowel disease, graft-versus-host disease and myocardial infarction 1, 20. T cells represent the primary effector cells for common autoimmune Carnitine palmitoyltransferase II diseases and for rejection of transplanted organs and tissues 21. Furthermore, activated memory T cells have been implicated see more in non-antigen-specific forms of tissue injury such as ischemia-reperfusion 22, 23. In

addition to the investigation of mechanisms underlying MSC inhibition of T-cell activation, attention has also been directed toward their influence on specific T-cell effector phenotypes including CD8+ CTLs and the Th1, Th2 and Treg sub-types of CD4+ T cells which may be more or less prominent in individual immune-mediated diseases 12, 24–26. In vitro and in vivo experimental evidence would suggest that MSCs are consistently suppressive of CTL- and Th1-mediated immune responses while being less inhibitory toward Th2-type responses and actively promoting Treg survival and expansion 9, 12, 27. Less well understood for each of these subsets are the relative effects of MSCs on naïve T cells undergoing primary activation compared with previously activated, or memory-phenotype, T cells. The recent description of an additional CD4+ T-cell subset, termed Th17 cells, has added further complexity to our understanding of cellular adaptive immunity 28. The Th17 effector phenotype is characterised by synthesis of a signature cytokine, IL-17A, in addition to IL-17F, IL-21, IL-22 and CCL20 29.