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

• Published in: Nature communications Vol. 10; no. 1; p. 354
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14; 38; 38/91; 42/70; 631/250/1619/554/1898/1271; 631/250/2152/569/2495; 631/250/38; 631/337/458/1524; 64/60; 82/58; 96/95; Acetylglucosamine - immunology; Acetylglucosamine - metabolism; Animals; Autoimmunity; Cell activation; Cell Lineage - genetics; Cell Lineage - immunology; Effector cells; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxp3 protein; Genes, Reporter; Homeostasis; Humanities and Social Sciences; Humans; Immunological tolerance; Immunoregulation; Inflammation; Interleukin 2; Interleukin-2 - genetics; Interleukin-2 - immunology; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Transgenic; multidisciplinary; N-Acetylglucosamine; O-GlcNAcylation; Primary Cell Culture; Protein deficiency; Protein Processing, Post-Translational; Proteins; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Regulators; Rodents; Science; Science (multidisciplinary); Self Tolerance; Signal Transduction; Signaling; Stability; Stat5 protein; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - immunology; Synergism; T cell receptors; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08300-3

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. The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity.