Background and Objectives Regulatory T (Treg) cells have a critical inhibitory effect in rheumatoid arthritis (RA) and are a potential target for therapies that suppress inflammation. Induction of Treg cells by mesenchymal stem cells (MSC) is proposed as one mechanism through which they exert immunosuppressive effects. The aim of this study was to evaluate the molecular mechanisms involved in the therapeutic potential of MSC in a murine model of RA and to better understand how the immune balance between Th1/Th17 and Treg cells is regulated following MSC injection. We focused our study on the role of Gilz which was recently described as an inhibitor of immune-inflammatory responses in RA.
Materials and Methods MSC deficient for Gilz (Gilz-/- MSC) were isolated from knockout mice. Their therapeutic effect after intravenous administration was compared to that of WT MSC in collagen-induced arthritis (CIA). The in vivo suppressive mechanism on effector T cell proliferation and the generation of regulatory T cells were also investigated.
Results Analysis of clinical and immunological parameters revealed that Gilz expression is crucial for the ability of MSC to control the progression of experimental arthritis. Moreover, we showed that while MSC reduce the frequency of Th1 and Th17 cells in the draining lymph nodes during arthritis development, Gilz-/- MSC did not. This significant decrease of Th1 and Th17 frequency following MSC injection was associated with the generation of IL-10-producing regulatory Th17 cells, an effect absent in Gilz-/- MSC treated mice.
Conclusion Our results demonstrate the requirement for Gilz in the therapeutic effect of MSC in a model of RA. We propose that the suppressive effect of MSC is mediated by the Gilz-dependent generation of new population of functional regulatory T cells bearing the CD4+RORγT+IL17LowIL10+ signature.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.