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CD39hi nature regulatory T cells are stable under inflammation condition and preventing xeno-GVHD

Jian Gu  Jie Zhao  Xuhao Ni  Hao Lu  Yunjie Lu  Kunpeng Wang  Zhou Bo  Ling Lu  
【摘要】:Autoimmune diseases are characterized by an imbalance between regulatory T(Treg)cells and effector T cell subsets such as Th1 and Th17 cells.Recent studies have demonstrated that thymus-derived naturally-occurring CD4+Foxp3+regulatory T cells(n Tregs)in both human and mouse are unstable and dysfunctional in the presence of pro-inflammatory cytokines.In this study,human CD39hi n Tregs and CD39low n Tregs were sorted from n Tregs 10 days after expansion.Foxp3 expression and suppressive activities were analyzed in vitro and in vivo using a standard assay in a humanized animal model.We find that in the presence of IL-1βand IL-6,CD4+CD39hi n Treg were stable,while CD4+CD39low n Tregs lose Foxp3 expression and transdifferentiate into Th1 or Th17 cells.Interestingly,human CD4+CD39hi n Treg,but not CD4+CD39low n Treg significantly protect xeno-graft versus host diseases(x GVHD)and only these cells maintained functional activity against x GVHD.Finally,STAT1 and STAT3 activation and CPG methylation were evaluated in CD39lown Tregs under pathological conditions.These results strongly implicated the physiological importance of CD39 expression in maintaining Foxp3 stability,and suggest that CD39hi n Tregs may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.

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