Duffy, Michelle M. and Pindjakova, Jana and Hanley, Shirley A. and McCarthy, Cathal and Weidhofer, Gudrun A. and Sweeney, Eva M. and English, Karen and Shaw, Georgina and Murphy, J. Mary and Barry, Frank P. and Mahon, Bernard P. and Belton, Orina and Ceredig, Rhodri and Griffin, Matthew D. (2011) 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. European Journal of Immunology, 41 (10). pp. 2840-2851. ISSN 1521-4141

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Abstract

Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naı¨ve T cells remain unclear. MSC influence on the differentiation of naı¨ve and memory CD41 T cells toward the Th17 phenotype was examined. CD41 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 naı¨ve- 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 naı¨ve 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.

Item Type:	Article
Keywords:	Immunosuppression; Mesenchymal stem cells; Stem cells; T helper cells; Th17 cells;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Institute of Immunology
Item ID:	7113
Identification Number:	https://doi.org/10.1002/eji.201141499
Depositing User:	Bernard Mahon
Date Deposited:	19 May 2016 11:18
Journal or Publication Title:	European Journal of Immunology
Publisher:	Wiley-VCH Verlag
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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