STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis

Abstract

Abstract Introduction Regulatory CD4+ T cells (Tregs) are pivotal for inhibition of autoimmunity. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology where contribution of Tregs is still unclear. Activation of the JAK‐STAT pathway critically modifies functions of Tregs. In PSC, we studied activation of STAT proteins and Treg functions in response to cytokines. Methods In 51 patients with PSC, 10 disease controls (chronic replicative hepatitis C), and 36 healthy controls we analyzed frequencies of Foxp3+CD25+CD127lowCD4+ Tregs, their expression of ectonucleotidase CD39, and cytokine‐induced phosphorylation of STAT1, 3, 5, and 6 using phospho‐flow cytometry. In parallel, we measured cytokines IFN‐gamma, interleukin (IL)‐6, IL‐2, and IL‐4 in serum via bead‐based immunoassays. Results In patients with PSC, ex vivo frequencies of peripheral Tregs and their expression of CD39 were significantly reduced (p < .05 each). Furthermore, serum levels of IFN‐gamma, IL‐6, IL‐2, and IL‐4 were markedly higher in PSC (p < .05 each). Unlike activation of STAT1, STAT5, and STAT6, IL‐6 induced increased phosphorylation of STAT3 in Tregs of PSC‐patients (p = .0434). Finally, STAT3 activation in Tregs correlated with leukocyte counts. Conclusions In PSC, we observed enhanced STAT3 responsiveness of CD4+ Tregs together with reduced CD39 expression probably reflecting inflammatory activity of the disease.

Keywords

• ectonucleotidase CD39
• interleukin‐6
• primary sclerosing cholangitis
• regulatory CD4+ T cells
• STAT proteins