Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions

Ling Lu, Qin Lan, Zhiyuan Li, Xiaohui Zhou, Jian Gu, Qiang Li, Julie Wang, Maogen Chen, Ya Liu, Yi Shen, David Brand, Bernhard Ryffel, David A. Horwitz, Francisco P. Quismorio, Zhongmin Liu, Bin Li, Nancy J. Olsen, Song Guo Zheng

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Abstract

Recent studies have demonstrated that thymus-derived naturally occurring CD4+Foxp3+ regulatory T cells (Tregs) in human and mouse may be unstable and dysfunctional in the presence of proinflammatory cytokines. All-trans RA (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. We hypothesize atRA stabilizes human natural Tregs (nTregs) under inflammatory conditions. atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encounters with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pretreated with atRA significantly enhanced their suppressive effects on xenograft-vs.-host diseases (xGVHDs), and atRA- but not rapamycin-pretreated nTregs sustained the functional activity against xGVHD after stimulation with IL-1/IL-6. atRA suppresses IL-1 receptor (IL-1R) up-regulation, accelerates IL-6R down-regulation, and diminishes their signaling events as well as prevents the up-regulation of STIP1 homology and U-Box containing protein 1 on Foxp3+ cells following IL-1/IL-6 stimulation. atRA also increases histone acetylation on Foxp3 gene promoter and CpG demethylation in the region of Foxp3 locus (i.e., Treg-specific demethylated region). These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number33
DOIs
StatePublished - Aug 19 2014
Externally publishedYes

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Regulatory T-Lymphocytes
Tretinoin
Interleukin-1
Interleukin-6
Up-Regulation
Th17 Cells
Th1 Cells
Interleukin-1 Receptors
Adoptive Transfer
Sirolimus
Acetylation
Vitamin A
Heterografts
Histones
Thymus Gland
Autoimmune Diseases
Cell Differentiation
Down-Regulation
Cytokines
Genes

All Science Journal Classification (ASJC) codes

  • General

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Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. / Lu, Ling; Lan, Qin; Li, Zhiyuan; Zhou, Xiaohui; Gu, Jian; Li, Qiang; Wang, Julie; Chen, Maogen; Liu, Ya; Shen, Yi; Brand, David; Ryffel, Bernhard; Horwitz, David A.; Quismorio, Francisco P.; Liu, Zhongmin; Li, Bin; Olsen, Nancy J.; Zheng, Song Guo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 33, 19.08.2014.

Research output: Contribution to journalArticle

Lu, L, Lan, Q, Li, Z, Zhou, X, Gu, J, Li, Q, Wang, J, Chen, M, Liu, Y, Shen, Y, Brand, D, Ryffel, B, Horwitz, DA, Quismorio, FP, Liu, Z, Li, B, Olsen, NJ & Zheng, SG 2014, 'Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 33. https://doi.org/10.1073/pnas.1408780111
Lu, Ling ; Lan, Qin ; Li, Zhiyuan ; Zhou, Xiaohui ; Gu, Jian ; Li, Qiang ; Wang, Julie ; Chen, Maogen ; Liu, Ya ; Shen, Yi ; Brand, David ; Ryffel, Bernhard ; Horwitz, David A. ; Quismorio, Francisco P. ; Liu, Zhongmin ; Li, Bin ; Olsen, Nancy J. ; Zheng, Song Guo. / Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 33.
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AU - Lu, Ling

AU - Lan, Qin

AU - Li, Zhiyuan

AU - Zhou, Xiaohui

AU - Gu, Jian

AU - Li, Qiang

AU - Wang, Julie

AU - Chen, Maogen

AU - Liu, Ya

AU - Shen, Yi

AU - Brand, David

AU - Ryffel, Bernhard

AU - Horwitz, David A.

AU - Quismorio, Francisco P.

AU - Liu, Zhongmin

AU - Li, Bin

AU - Olsen, Nancy J.

AU - Zheng, Song Guo

PY - 2014/8/19

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N2 - Recent studies have demonstrated that thymus-derived naturally occurring CD4+Foxp3+ regulatory T cells (Tregs) in human and mouse may be unstable and dysfunctional in the presence of proinflammatory cytokines. All-trans RA (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. We hypothesize atRA stabilizes human natural Tregs (nTregs) under inflammatory conditions. atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encounters with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pretreated with atRA significantly enhanced their suppressive effects on xenograft-vs.-host diseases (xGVHDs), and atRA- but not rapamycin-pretreated nTregs sustained the functional activity against xGVHD after stimulation with IL-1/IL-6. atRA suppresses IL-1 receptor (IL-1R) up-regulation, accelerates IL-6R down-regulation, and diminishes their signaling events as well as prevents the up-regulation of STIP1 homology and U-Box containing protein 1 on Foxp3+ cells following IL-1/IL-6 stimulation. atRA also increases histone acetylation on Foxp3 gene promoter and CpG demethylation in the region of Foxp3 locus (i.e., Treg-specific demethylated region). These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.

AB - Recent studies have demonstrated that thymus-derived naturally occurring CD4+Foxp3+ regulatory T cells (Tregs) in human and mouse may be unstable and dysfunctional in the presence of proinflammatory cytokines. All-trans RA (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. We hypothesize atRA stabilizes human natural Tregs (nTregs) under inflammatory conditions. atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encounters with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pretreated with atRA significantly enhanced their suppressive effects on xenograft-vs.-host diseases (xGVHDs), and atRA- but not rapamycin-pretreated nTregs sustained the functional activity against xGVHD after stimulation with IL-1/IL-6. atRA suppresses IL-1 receptor (IL-1R) up-regulation, accelerates IL-6R down-regulation, and diminishes their signaling events as well as prevents the up-regulation of STIP1 homology and U-Box containing protein 1 on Foxp3+ cells following IL-1/IL-6 stimulation. atRA also increases histone acetylation on Foxp3 gene promoter and CpG demethylation in the region of Foxp3 locus (i.e., Treg-specific demethylated region). These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated autoimmune and inflammatory diseases.

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