title: Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor.
abstract: 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 CD4(+)  T cells toward the Th17 phenotype was examined. CD4(+)  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 memory-phenotype 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 cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.
authors.affiliation: Regenerative Medicine Institute, National Centre for Biomedical Engineering Science and School of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Duffy
authors.forename: Jana
authors.initials: J
authors.lastname: Pindjakova
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Hanley
authors.forename: Cathal
authors.initials: C
authors.lastname: McCarthy
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Weidhofer
authors.forename: Eva M
authors.initials: EM
authors.lastname: Sweeney
authors.forename: Karen
authors.initials: K
authors.lastname: English
authors.forename: Georgina
authors.initials: G
authors.lastname: Shaw
authors.forename: J Mary
authors.initials: JM
authors.lastname: Murphy
authors.forename: Frank P
authors.initials: FP
authors.lastname: Barry
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Mahon
authors.forename: Orina
authors.initials: O
authors.lastname: Belton
authors.forename: Rhodri
authors.initials: R
authors.lastname: Ceredig
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D007213:Indomethacin / Q000494:pharmacology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000378:metabolism*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone; D007213:Indomethacin