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 journalArticlepeer-review

46 Scopus citations


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
Issue number1
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank Dr. Hu Zeng for discussions and suggestions, Dr. Xiaoyong Yang for providing the Ogtfl/fl mice, Dr. Richard Moriggl for providing STAT5 vectors, Dr. Alexander Rudensky for providing the Rosa26Stat5b-CA mice, Dr. Jop van Berlo for providing the Rosa26tdTomato Cre-reporter mice, and Dr. Doug Mashek for providing the Ubc-Cre/ ERT2+ mice. We thank the UMN Flow Cytometry Resource for cell sorting, Juan E. Abrahante Lloréns from University of Minnesota Informatics Institute for bioinformatic analysis. This work was supported by NIH grant R01 AI139420, R21 AI140109, and American Diabetes Association grant 1–18-IBS-167 to H.-B.R., R37 AI39560 to K.A.H., R01 AI124512 to M.A.F., R01 HL11879 and P01 CA065493 to B.R.B., S10 OD010731 to L.E.B., and a grant from the Adelson Medical Research Foundation to A.L.B. The Thermo Scientific Fusion Lumos was funded by the UCSF Program for Breakthrough Biomedical Research (PBBR).

Publisher Copyright:
© 2019, The Author(s).


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