Human CD39⁺ T_reg Cells Express Th17-Associated Surface Markers and Suppress IL-17 via a Stat3-Dependent Mechanism

Human CD4⁺ T regulatory cells (T_regs) are a population of phenotypically and functionally diverse cells that downregulate inflammatory and autoimmune responses. As Th17 cells play an important role in the pathogenesis of autoimmune diseases, it is critical to elucidate the mechanisms regulating these cells. In this study, we examined the molecular basis underlying the phenotypic and functional diversity of human T_regs expressing the ectonucleotidase CD39. CD4⁺CD25^hiCD39⁺ T_regs inhibit the proliferative response and the secretion of IL-17 and IFN-γ of autologous CD4⁺ T effector cells, while CD4⁺CD25^hiCD39^- T_regs only suppress IFN-γ production. We demonstrate that activated human CD4⁺CD25^hiCD39⁺ T_regs express the Th17-associated surface markers CCR6 and IL-23R, and phosphorylate the transcription factor Stat3. Moreover, suppression of IL-17 by CD4⁺CD25^hiCD39⁺ T_regs occurs via a Stat3-dependent mechanism as inhibition of Stat3 activation in the CD39⁺ T_regs reverses their ability to suppress IL-17. CD4⁺CD25^hiCD39^- T_regs are not endowed with the ability to inhibit IL-17 as they do not upregulate CCR6 or the IL-23R, and furthermore, they secrete IL-17. Our findings provide the first evidence that human T_reg functional diversity is matched to the type of immune response being regulated and reveal a new role for Stat3 in controlling T_reg function.