TY - JOUR
T1 - Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions
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 D.
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
Y1 - 2014/8/19
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.
UR - http://www.scopus.com/inward/record.url?scp=84906308941&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906308941&partnerID=8YFLogxK
U2 - 10.1073/pnas.1408780111
DO - 10.1073/pnas.1408780111
M3 - Article
C2 - 25099355
AN - SCOPUS:84906308941
SN - 0027-8424
VL - 111
SP - E3432-E3440
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -