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 () and Hai-Bin Ruan ()
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Bing Liu: University of Minnesota
Oscar C. Salgado: University of Minnesota
Sangya Singh: University of Minnesota
Keli L. Hippen: University of Minnesota
Jason C. Maynard: University of California, San Francisco
Alma L. Burlingame: University of California, San Francisco
Lauren E. Ball: Medical University of South Carolina
Bruce R. Blazar: University of Minnesota
Michael A. Farrar: University of Minnesota
Kristin A. Hogquist: University of Minnesota
Hai-Bin Ruan: University of Minnesota

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08300-3

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