Résumé
The therapeutic effect of mesenchymal stem cells (MSCs) in multiple sclerosis (MS) andthe experimental autoimmune encephalomyelitis (EAE) model has been well described.This effect is, in part, mediated through the inhibition of IL17-producing cells and thegeneration of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα,and IL1β have been shown to enhance MSCs immunosuppressive function, the roleof IL17 remains poorly elucidated. The aim of this study was, therefore, to investigatethe role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing onTh17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro,we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation anddifferentiation is partially dependent on IL17RA expression. This was associated witha reduced expression level of MSCs immunosuppressive mediators such as VCAM1,ICAM1, and PD-L1 in IL17RA−/− MSCs as compared to wild-type (WT) MSCs. In theEAE model, we demonstrated that while WT MSCs significantly reduced the clinicalscores of the disease, IL17RA−/− MSCs injected mice exhibited a clinical worsening ofthe disease. The disability of IL17RA−/− MSCs to reduce the progression of the diseaseparalleled the inability of these cells to reduce the frequency of Th17 cells in the draininglymph node of the mice as compared to WT MSCs. Moreover, we showed that thetherapeutic effect of MSCs was correlated with the generation of classical Treg bearingthe CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveala novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAEand suggest that the modulation of IL17RA in MSCs could represent a novel method toenhance their therapeutic effect in MS.