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O-GlcNAcylation maintains lineage stability of regulatory T cells.

Regulatory T (Treg) cells are required to maintain self-tolerance, mediate inflammatory responses and regulate tissue homeostasis. Forkhead box P3 (FOXP3) plays an important role in stabilising the lineage identity of mature Treg cells. Constituent expression of the transcription factor FOXP3 has lineage-defining role in mature Treg cells. On the other hand, T cell receptor (TCR) signalling and interleukin-2 (IL-2)/STAT5 activation mediate the effector functions of Treg cells. In developing Treg cells, the expression of FOXP3 is induced by TCR and IL-2R activation.   However, the mechanism of cross-talk between the two signalling pathways to maintain the stability and functions of Treg cells is unknown. 

The response of Treg cells to external signals can be modified by post-translational modification. Amongst phosphorylation, acetylation and ubiquitination, O-linked N-Acetylglucosamine (O-GlcNAc) mediated modification of serine and threonine residues (O-GlcNAcylation) has been recently identified as a modulator of protein stability. The addition and removal of O-GlcNAc is mediated by O-GlcNAc transferase (OGT) and O-GlcNAcases (OGA) respectively. 

Previous studies have shown that T cells upregulate O-GlcNAcylation upon activation during an immune response. Inhibition of OGT in Treg cells in mice resulted in aggressive autoimmune syndrome due to lineage instability reduced effector function of Treg cells. However, pharmacological induction of O-GlcNAcylation suppresses Treg cells in humans and inhibition of OGA with thiamet G (from Carbosynth) increased O-GlcNAcylated FOXP3.  Thus, overexpressing OGT and inhibiting OGA have stabilising effects on FOXP3, whilst the converse occurs when OGA is overexpressed and OGT is inhibited. 

The degradation of FOXP3 is regulated by ubiquitination, mediated by the ubiquitin ligase STUB1 and deubiquitinase USP7. It is therefore postulated that O-GlcNAcylation overcomes the ubiquitination of FOXP3 protein, stabilising it. Assessing the effect of FOXP3 O-GlcNAcylation on IL-2/STAT5 signalling revealed reduced signalling in OGT-deficient Treg cells.  Furthermore, re-instating STAT5 signalling improved Treg lineage stability and effector functions. 

The stability of Treg cell has implications on Treg cell immunotherapy. Overall, observations from this study suggest that O-GlcNAcylation stabilises FOXP3 and activates STAT5 to control lineage stability and effector functions of Treg cells. Furthermore, it is predicted that O-GlcNAcylation protects FOXP3 from degradation, either by inhibiting ubiquitin ligase STUB1 or inducing deubiquitinase USP7. Thus, pharmacological inhibitors of OGA, such as thiamet G, that increase O-GlcNAcylation of Treg have potential benefits for the application of Treg cells in autoimmune and inflammatory diseases. 

For further information, please refer to the original paper: Liu B et al (2019).

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