Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions

Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Thl 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 CD...

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Bibliographic Details
Published inCellular & molecular immunology Vol. 14; no. 6; pp. 521 - 528
Main Authors Gu, Jian, Ni, Xuhao, Pan, Xiongxiong, Lu, Hao, Lu, Yunjie, Zhao, Jie, Guo Zheng, Song, Hippen, Keli L, Wang, Xuehao, Lu, Ling
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.06.2017
Nature Publishing Group
Subjects
Antibodies
Autoimmune diseases
Biomedical and Life Sciences
Biomedicine
CD4 antigen
CpG islands
Demethylation
Effector cells
eg细胞
Forkhead protein
Foxp3 protein
Helper cells
IL-1β
Immunology
Immunoregulation
Interleukin 6
Lymphocytes T
Medical Microbiology
Microbiology
research-article
Stat1 protein
Stat3 protein
T细胞亚群
Vaccine
Xenografts
人类
炎性细胞因子
稳定性
自身免疫性疾病
调节性T细胞
CD39
Tregs
stability
xeno-GVHD
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Summary:Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Thl 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 CD39hi Tregs and CD39low Tregs 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＋CD39hi Tregs maintained stable forkhead box protein 3 expression, whereas CD4＋CD39low Tregs lost Foxp3 expression and trans-differentiated into Thl or Th17 cells. Decreased IL-1βR and IL-6R expression on the CD39hi Tregs 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＋CD39hi Tregs but not CD4＋CD39low Tregs protected against xenograft versus host disease in model mice. These results strongly implied the physiological importance of CD39 expression and suggested that manipulation of CD39hi Tregs might represent a novel strategy for the treatment of autoimmune diseases.
Bibliography:11-4987/R
CD39; stability; Tregs; xeno-GVHD
Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Thl 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 CD39hi Tregs and CD39low Tregs 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＋CD39hi Tregs maintained stable forkhead box protein 3 expression, whereas CD4＋CD39low Tregs lost Foxp3 expression and trans-differentiated into Thl or Th17 cells. Decreased IL-1βR and IL-6R expression on the CD39hi Tregs 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＋CD39hi Tregs but not CD4＋CD39low Tregs protected against xenograft versus host disease in model mice. These results strongly implied the physiological importance of CD39 expression and suggested that manipulation of CD39hi Tregs might represent a novel strategy for the treatment of autoimmune diseases.
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These authors contributed equally to this work.
ISSN:1672-7681
2042-0226
DOI:10.1038/cmi.2016.30