Benefits Selleck Alpelisib of MSC administration in models of autoimmunity and allotransplantation indicate corresponding in vivo effects 2, 4, 14, 32, 33. Nonetheless, some basic issues regarding MSC/T-cell interactions remain incompletely elucidated including the relative potency of MSC suppression of primary compared with secondary T-cell activation, MSC influence on individual T-cell effector programmes, the relative importance of the wide diversity of mediators that have been linked with
T-cell inhibition and the balance between direct T-cell effects and indirect inhibition mediated via APCs. In the current study we have addressed such issues with a focus on the Th17 differentiation pathway – a pro-inflammatory Th cell effector phenotype with pathogenic potential in a range of immune-mediated diseases 28, 29. We demonstrate that low numbers of MSCs are capable of suppressing de novo Th17 differentiation through a mechanism that is initiated most potently by MSC/T-cell contact but is subsequently mediated by PGE2 acting via the EP4 receptor. In contrast
to other reported T-cell inhibitory phenomena 17, 19, we find that IFN-γ-mediated triggering of MSCs was not necessary for Th17 suppression. Furthermore, we demonstrate suppression by MSCs of Th17 differentiation from both naïve- and memory-phenotype precursors as well AG14699 as inhibition of IL-17A production by naturally occurring effector-memory Th17 cells in a model of acute tissue inflammation. Our initial observations of MSC effects on in vitro-generated Th17 cells from mouse both confirm and extend results recently reported by Ghannam et al. for human cells 9. In agreement with this study, we observed that mouse MSCs inhibited the primary differentiation of Th17 cells from naïve precursors and that MSC co-culture resulted in reduced IL-17A production by T cells during MSC-free re-stimulation 9. Regarding the question of whether MSC suppressive effects are exerted directly upon CD4+ T cells undergoing Th17
differentiation, experiments in an APC-culture system effectively rule out an intermediary role for DCs, macrophages or other accessory cells. As only a fraction of the CD4+ T cells within primary cultures were IL-17A+ by intracellular staining at a given time, we cannot definitively Protirelin rule out a role for an additional T-cell population in suppressing the Th17 differentiation programme. Nonetheless, cross-regulation by Th1 or Th2 effectors during primary Th17 induction cultures is highly unlikely given the continuous blockade of IFN-γ and IL-4. Furthermore, and in contrast to the findings of Ghannam et al. 9, we did not detect induction of FOXP3+ or IL-10+ T cells in experiments carried out using FACS-purified, naïve-phenotype CD4+ T cells co-cultured with MSCs under Th17-skewing conditions (data not shown).