Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells

Varun Nair, Kwon Ik Oh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.

Original languageEnglish
Pages (from-to)918-924
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume450
Issue number1
DOIs
Publication statusPublished - 18 Jul 2014
Externally publishedYes

Fingerprint

T-cells
Regulatory T-Lymphocytes
Interleukin-2
Down-Regulation
Epigenomics
Dioxygenases
Intrinsic Factor
Cues
Up-Regulation
Cytokines
Inflammation

Keywords

  • Demethylation
  • Foxp3
  • Interleukin-2
  • Regulatory T cells
  • Tolerance

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. / Nair, Varun; Oh, Kwon Ik.

In: Biochemical and Biophysical Research Communications, Vol. 450, No. 1, 18.07.2014, p. 918-924.

Research output: Contribution to journalArticle

@article{54596fe95d9843369aa05c39de22a93f,
title = "Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells",
abstract = "Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.",
keywords = "Demethylation, Foxp3, Interleukin-2, Regulatory T cells, Tolerance",
author = "Varun Nair and Oh, {Kwon Ik}",
year = "2014",
month = "7",
day = "18",
doi = "10.1016/j.bbrc.2014.06.110",
language = "English",
volume = "450",
pages = "918--924",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells

AU - Nair, Varun

AU - Oh, Kwon Ik

PY - 2014/7/18

Y1 - 2014/7/18

N2 - Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.

AB - Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.

KW - Demethylation

KW - Foxp3

KW - Interleukin-2

KW - Regulatory T cells

KW - Tolerance

UR - http://www.scopus.com/inward/record.url?scp=84904749191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904749191&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2014.06.110

DO - 10.1016/j.bbrc.2014.06.110

M3 - Article

C2 - 24984151

AN - SCOPUS:84904749191

VL - 450

SP - 918

EP - 924

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -