The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation

Bing Liu, Oscar C. Salgado, Sangya Singh, Keli L. Hippen, Jason C. Maynard, Alma L. Burlingame, Lauren E. Ball, Bruce R. Blazar, Michael A. Farrar, Kristin A. Hogquist, Hai Bin Ruan

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Regulatory T (Treg) cells control self-tolerance, inflammatory responses and tissue homeostasis. In mature Treg cells, continued expression of FOXP3 maintains lineage identity, while T cell receptor (TCR) signaling and interleukin-2 (IL-2)/STAT5 activation support the suppressive effector function of Treg cells, but how these regulators synergize to control Treg cell homeostasis and function remains unclear. Here we show that TCR-activated posttranslational modification by O-linked N-Acetylglucosamine (O-GlcNAc) stabilizes FOXP3 and activates STAT5, thus integrating these critical signaling pathways. O-GlcNAc-deficient Treg cells develop normally but display modestly reduced FOXP3 expression, strongly impaired lineage stability and effector function, and ultimately fatal autoimmunity in mice. Moreover, deficiency in protein O-GlcNAcylation attenuates IL-2/STAT5 signaling, while overexpression of a constitutively active form of STAT5 partially ameliorates Treg cell dysfunction and systemic inflammation in O-GlcNAc deficient mice. Collectively, our data demonstrate that protein O-GlcNAcylation is essential for lineage stability and effector function in Treg cells.

Original languageEnglish (US)
Article number354
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

    Fingerprint

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this