IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells

Abstract

Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3+ T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1α) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1β on Treg differentiation. Chemical stabilization of HIF-1α by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1β-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1α dependent, suggesting that targeting HIF-1α could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1β deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate.

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity

“…We also did not observe a significant induction of Foxp3 + CD25 + Tregs by TEPP-46 in EAE mice, suggesting that generation of Tregs in vivo is not the main beneficial effect of TEPP-46 on disease development. Of note, previous work showed that inhibition of mTORC1, Myc, and HIF-1a all induce the development of Foxp3 + T cells under inflammatory conditions, mainly by blocking the engagement of glycolysis (Wei et al, 2016;Shi et al, 2011;Dang et al, 2011;Feldhoff et al, 2017). However, other studies have shown that glycolysis and mTORC1/HIF-1a activity could favor the generation of Tregs, especially in vivo (Clambey et al, 2012;Zeng et al, 2013;Wu et al, 2014;Procaccini et al, 2016).…”

Treg programming and therapeutic reprogramming in cancer

“…Low oxygen tension, combined with TCR activation, can stabilize hypoxia‐inducible factor 1‐ α (HIF1‐ α ), and this may promote Foxp3 expression in vitro . However, a number of studies also indicate that expression of HIF1‐ α impairs Treg stability due to its transcriptional induction of glycolytic genes and its direct binding to Foxp3, which can drive Foxp3 degradation . Supporting the latter hypothesis, the oxygen‐sensing prolyl‐hydroxylase (PHD) proteins, which are suppressors of HIF1‐ α , are required to induce Treg programming in metastatic niches .…”

“…[73][74][75] However, a number of studies also indicate that expression of HIF1-a impairs Treg stability due to its transcriptional induction of glycolytic genes and its direct binding to Foxp3, which can drive Foxp3 degradation. [76][77][78] Supporting the latter hypothesis, the oxygen-sensing prolylhydroxylase (PHD) proteins, which are suppressors of HIF1-a, are required to induce Treg programming in metastatic niches. 79 Similarly, targeted deletion of the HIF1-a E3 ubiquitin ligase Von Hippel-Lindau (VHL) in Tregs leads to elevated HIF1-a that directly binds to the promoter of the Ifng gene and induces IFN-c expression in Tregs, resulting in their conversion into Th1-like cells.…”

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

“…The detrimental role of HIF‐1α in Tregs differentiation is not limited to murine Tregs. Increased HIF‐1α expression, by either DMOG or IL‐1β, impairs human Tregs differentiation . DMOG inhibits mitochondrial respiration and increases glycolysis in human Tregs, representing a possible mechanism by which HIF‐1α inhibits Treg development.…”