title: Human embryonic stem cells prevent T-cell activation by suppressing dendritic cells function via TGF-beta signaling pathway.
abstract: Human embryonic stem cells (hESCs) represent a potential source of transplantable cells for regenerative medicine, but development of teratoma even in syngenic recipients represents a critical obstacle to safe stem cell-based therapies. We hypothesized that hESCs escape the immune surveillance by regulating the environmental immune system. Using cocultures of hESCs with allogenic peripheral blood mononuclear cells, we demonstrated that hESCs prevent proliferation and activation of human CD4+ T lymphocytes, an effect dependent upon monocytes. Altered expression of key signaling molecules responsible for the crosstalk of monocytes with T cells was detected in the presence of hESCs. Analyzing the mechanism of action, we demonstrated that hESCs were able to downregulate intracellular glutathione levels in both monocytes and CD4+ cells by suppressing glutamate cysteine ligase expression and to alter MHCII and CD80 expression in monocytes. These effects were achieved at least partially via TGF-beta signaling, and both monocyte phenotype and GCLC expression were affected by Caspase-3 proteolytic activity. Altogether, our results demonstrate a novel immune-suppressive mechanism used by hESCs.
authors.affiliation: INSERTECH Stem Cell Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; Stem Cell Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Lucy
authors.initials: L
authors.lastname: Leshansky
authors.forename: Daniel
authors.initials: D
authors.lastname: Aberdam
authors.forename: Joseph
authors.initials: J
authors.lastname: Itskovitz-Eldor
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology*; D018920:Coculture Techniques / Q000379:methods; D003713:Dendritic Cells / Q000166:cytology*; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D009000:Monocytes / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D016212:Transforming Growth Factor beta
keywords: Embryonic stem cells; Immunosuppression; T cells; TGF-β