Control of Foxp3 stability through modulation of TET activity

Research output: Contribution to journalArticle

Researchers

  • Xiaojing Yue
  • Sara Trifari
  • Tarmo Äijö
  • Ageliki Tsagaratou
  • William A. Pastor
  • Jorge A. Zepeda-Martínez
  • Chan Wang J Lio
  • Xiang Li
  • Yun Huang
  • Pandurangan Vijayanand
  • Harri Lähdesmäki

  • Anjana Rao

Research units

  • La Jolla Institute for Allergy and Immunology
  • Sanford Consortium for Regenerative Medicine
  • University of California San Diego

Abstract

Ten-eleven translocation (TET ) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/ Tet3 to increase the stability of Foxp3 expression in TGF -β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.

Details

Original languageEnglish
Pages (from-to)377-397
Number of pages21
JournalJOURNAL OF EXPERIMENTAL MEDICINE
Volume213
Issue number3
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

ID: 1923707