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

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

doi:10.1038/s41467-019-08300-3

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.

Highlights

Regulatory T (Treg) cells control self-tolerance, inflammatory responses and tissue homeostasis
The transcription factor B lymphocyte-induced maturation protein (BLIMP)-1 is common to all effector Treg (eTreg) cells[38], and we found that BLIMP-1-upregulated genes were enriched in O-GlcNAc transferase (OGT)-sufficient Treg cells, while BLIMP1-downregulated genes were enriched in OGT-deficient Treg cells (Fig. 6b, c), suggesting that OGT maintains a transcriptional program similar to that of BLIMP-1+ eTreg cells
In mature Treg cells, Forkhead box P3 (FOXP3) expression and signals from T cell receptor (TCR) and interleukin-2 receptor (IL-2R) are continuously required for Treg lineage stability and suppressive function[9,10,16,17,18,46]

Summary

Introduction

Regulatory T (Treg) cells control self-tolerance, inflammatory responses and tissue homeostasis. IL-2R and downstream STAT5 signaling are indispensable for eTreg cell differentiation and function by controlling a distinct set of genes that are separable from those regulated by TCR signaling[18]. It is still unclear how Treg cells integrate these pathways to maintain the suppressive program. T cell-specific ablation of OGT resulted in an increase of apoptotic T cells[28], and blocked T cell progenitor renewal, malignant transformation and peripheral T cell clonal expansion[29] These data demonstrate that protein O-GlcNAcylation links TCR signaling to T cell differentiation and function; the role of O-GlcNAcylation in Treg cells has not been studied

Methods

Results

Conclusion