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

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.

O-GlcNAcylation and its role in the immune system

“…Recent studies indicated that O-GlcNAcylation is implicated in both differentiation and homeostasis of Th17 and Treg cells (Fig. 2d, lower right panel) [140][141][142]. Administration of Thiamet-G increased the binding of RORγt, a pivotal transcription factor for commitment of the Th17 lineage [143], to Il-17 promoter and therefore promotes IL-17 production and Th17 differentiation.…”

“…It has been reported that FOXP3 is stabilized by O-GlcNAcylation, and that O-GlcNAcylation is required for IL-2/STAT5 signalingmediated FOXP3 expression. Depletion of Ogt in Treg cells in mice dramatically reduced Treg lineage stability, which resulted in a severe autoimmune phenotype [141]. Thus, O-GlcNAcylation is required for the maintenance of lineage stability and regulatory function of Treg cells.…”

Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

“…The immunosuppressive features of tumor lesions participate not only as one of the major players inducing cancer progression but also a big challenge for effective immunotherapy. It has been found that immunosuppression associated with chronic inflammatory factors, such as growth factors, cytokines, and chemokines is generated by stroma and tumor cells [14,15]. Multiple immune cells coexist and interact in a complex series of pathways that ultimately lead to tumor carcinogenesis.…”

Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma

“…Increasing studies highlight the immunosuppressive functions of TME in favoring the HCC progression and potential drug resistance. The initiation of such immune-tolerant microenvironment is mediated by numerous inflammatory factors such as growth factors, cytokines, chemokines generated by multiple cell types co-existed and interacted in TME [ 92 , 93 ]. Of them, the key constructive cells include TAMs, marrow-derived suppressor cells (MDSCs), tumor-associated neutrophils, CAFs, as well as infiltrating T cells and natural killer (NK) cells [ 94 ].…”