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

  • Author(s): Liu, Bing
  • Salgado, Oscar C
  • Singh, Sangya
  • Hippen, Keli L
  • Maynard, Jason C
  • Burlingame, Alma L
  • Ball, Lauren E
  • Blazar, Bruce R
  • Farrar, Michael A
  • Hogquist, Kristin A
  • Ruan, Hai-Bin
  • et al.
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.

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