Peer-Reviewed Journal Details
Mandatory Fields
Duffy, MM;Pindjakova, J;Hanley, SA;McCarthy, C;Weidhofer, GA;Sweeney, EM;English, K;Shaw, G;Murphy, JM;Barry, FP;Mahon, BP;Belton, O;Ceredig, R;Griffin, MD
2011
October
European Journal of Immunology
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
Published
116 ()
Optional Fields
EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ISCHEMIA-REPERFUSION INJURY DENDRITIC CELLS INTERFERON-GAMMA EXPANSION PROLIFERATION MICE INFLAMMATION LYMPHOCYTES INDUCTION
41
2840
2851
Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naive T cells remain unclear. MSC influence on the differentiation of naive 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 naive- 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 naive 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.
MALDEN
0014-2980
10.1002/eji.201141499
Grant Details