Defective immunosuppressive function of Treg cells in visceral adipose tissue in MIF deficient mice.

• MIF deletion promotes obesity and VAT inflammation. • Treg cells are numerous in MIF−/− VAT. • Insufficient IL-10 and TGF-β expression/secretion in MIF−/− VAT. • Significantly lower levels of STAT3 and IL-33 in MIF−/− VAT. • MIF is necessary for immunosuppressive Treg action in VAT. Obesity, a global health problem nowadays, is a state of low-grade chronic inflammation of adipose tissue (AT) associated with increased adipocyte growth and proliferation and immune cell polarization towards an inflammatory phenotype within the stromal vascular fraction (SVF). Pro-inflammatory cells in the AT produce mediators of inflammation (IL-1β, TNF, macrophage migration inhibitory factor – MIF), thereby surpassing the anti-inflammatory response mediated by IL-10 and TGF-β, cytokines produced by regulatory T (Treg) cells. In this study we demonstrate that the absence of the pro-inflammatory cytokine MIF led to obesity and inflammation in the visceral AT (VAT) in 6 months old MIF−/− mice. Besides the increment of pro-inflammatory AT macrophages and the enhanced production of TNF and IL-1β, VAT of MIF−/− mice contained increased numbers of Treg cells. In situ proliferation of Treg cells did not differ between MIF−/− and wild type mice, but Treg cells isolated from the VAT of MIF-deficient mice, and not from the cervical lymph nodes, exhibited lower expression and production of IL-10 and TGF-β. Additionally, SVF cells had significantly lower levels of STAT3 and IL-33, altogether indicating that VAT Treg cells in MIF−/− mice, albeit abundantly present, are not fully functional. These results indicate that MIF is a new regulator of VAT Treg cell function, necessary for their immunosuppressive activities. [ABSTRACT FROM AUTHOR]