title: Human CD39hiregulatory T cells present stronger stability and function under inflammatory conditions.
abstract: Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Th1 and Th17 cells. Studies have confirmed that natural CD4+Foxp3+Tregs were unstable and dysfunctional in the presence of pro-inflammatory cytokines. In the current study, human CD39hiTregs and CD39lowTregs were sorted from Tregs in vitro after 7 days of expansion. The functions of both Treg subsets were investigated under inflammatory conditions in vitro and in vivo. In the presence of IL-1β and IL-6, cultured CD4+CD39hiTregs maintained stable forkhead box protein 3 expression, whereas CD4+CD39lowTregs lost Foxp3 expression and trans-differentiated into Th1 or Th17 cells. Decreased IL-1βR and IL-6R expression on the CD39hiTregs was the primary mechanism responsible for Treg stability. In addition, reduced activation of downstream molecules, such as STAT1 and STAT3, through the modulation of CpG demethylation played an important role. Finally, human CD4+CD39hiTregs but not CD4+CD39lowTregs protected against xenograft versus host disease in model mice. These results strongly implied the physiological importance of CD39 expression and suggested that manipulation of CD39hiTregs might represent a novel strategy for the treatment of autoimmune diseases.
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuhao
authors.initials: X
authors.lastname: Ni
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiongxiong
authors.initials: X
authors.lastname: Pan
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.|University of Minnesota Cancer Center and Division of Bone Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Rheumatology, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Guo Zheng
authors.affiliation: University of Minnesota Cancer Center and Division of Bone Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Keli L
authors.initials: KL
authors.lastname: Hippen
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Translational Medicine Research Center, Affiliated Jiangning Hospital, and Liver Transplantation Center, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D015551:Autoimmunity; D002478:Cells, Cultured; D019175:DNA Methylation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053583:Interleukin-1beta; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D001081:Apyrase; C067869:CD39 antigen