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

Jian Gu, Xuhao Ni, Xiongxiong Pan, Hao Lu, Yunjie Lu, Jie Zhao, Song Guo Zheng, Keli L. Hippen, Xuehao Wang, Ling Lu

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 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 Th1 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.

Original languageEnglish (US)
Pages (from-to)521-528
Number of pages8
JournalCellular and Molecular Immunology
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2017

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Th17 Cells
Th1 Cells
Regulatory T-Lymphocytes
Autoimmune Diseases
Forkhead Transcription Factors
T-Lymphocyte Subsets
Interleukin-1
Heterografts
Interleukin-6
Cytokines
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Gu, Jian ; Ni, Xuhao ; Pan, Xiongxiong ; Lu, Hao ; Lu, Yunjie ; Zhao, Jie ; Zheng, Song Guo ; Hippen, Keli L. ; Wang, Xuehao ; Lu, Ling. / Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. In: Cellular and Molecular Immunology. 2017 ; Vol. 14, No. 6. pp. 521-528.
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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 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 Th1 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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Gu, J, Ni, X, Pan, X, Lu, H, Lu, Y, Zhao, J, Zheng, SG, Hippen, KL, Wang, X & Lu, L 2017, 'Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions', Cellular and Molecular Immunology, vol. 14, no. 6, pp. 521-528. https://doi.org/10.1038/cmi.2016.30

Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. / Gu, Jian; Ni, Xuhao; Pan, Xiongxiong; Lu, Hao; Lu, Yunjie; Zhao, Jie; Zheng, Song Guo; Hippen, Keli L.; Wang, Xuehao; Lu, Ling.

In: Cellular and Molecular Immunology, Vol. 14, No. 6, 01.06.2017, p. 521-528.

Research output: Contribution to journalArticle

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AU - Gu, Jian

AU - Ni, Xuhao

AU - Pan, Xiongxiong

AU - Lu, Hao

AU - Lu, Yunjie

AU - Zhao, Jie

AU - Zheng, Song Guo

AU - Hippen, Keli L.

AU - Wang, Xuehao

AU - Lu, Ling

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AB - 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 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 Th1 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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