S-2HG is an immunometabolite that shapes the T-cell response

Abstract

The field of immunometabolism has expanded rapidly over the past several years, and it is now clear that specific alterations to the metabolism of immune cells occur in response to endogenous and exogenous stimuli in order to tailor the biochemistry of cells to their functional requirements and microenvironmental context. 1 Major findings in T cells have shown that, upon activation, a metabolic response is engaged, resulting in a dramatic increase in glycolysis to support rapid proliferation. Subsequently, during the formation of memory T cells, metabolism shifts away from glycolysis and back towards oxidative phosphorylation fueled by fatty acid oxidation. The mechanisms responsible for this change overlap significantly with the adaptive response to changes in oxygen concentration, but the details are not completely understood.The two chiral forms of the metabolite 2-hydroxyglutarate, R-2HG and S-2HG, are produced in mammalian cells, and are usually maintained at low levels in cells and body fluids via the activity of dedicated dehydrogenase enzymes that convert these compounds to ɑ-ketoglutarate (ɑ-KG). Gain-of-function mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) lead to the inappropriate production and accumulation of R-2HG, which is thought to contribute to tumorigenesis in several tissues by altering epigenetic state and metabolism. 2 The discovery of these mutations has led to a concerted effort to understand the tumorigenic mechanisms underlying R-2HG accumulation. However, little is known about the physiological roles of R-2HG or S-2HG. The ability of these molecules to inhibit a broad class of 2-oxoglutarate-dependent dioxygenases, including key epigenetic regulatory enzymes, suggests that they may have roles in altering the function and fate of specific cells.It has been shown previously that S-2HG increases upon exposure of cells to hypoxia or in situations where mitochondria are dysfunctional. [3][4][5] Under these conditions, S-2HG can be produced by malate dehydrogenase (MDH), lactate dehydrogenase A (LDHA), and even wild-type IDH in certain cell types. These previous studies suggest that accumulation of S-2HG plays a role in the process of hypoxic adaptation by causing epigenetic alterations that are necessary for appropriate reprogramming of metabolism. Interestingly, these previous reports found only a minor role for the HIF transcription factor, often considered the master regulator of the hypoxic response, in mediating the observed increases in S-2HG.In the current issue of Nature, Tyrakis et al. 6 report on the physiological role of S-2HG in T cells. T cells display a high degree of metabolic flexibility as their needs change during periods of rapid proliferation and cytolytic activity, and these metabolic changes are required for T-cell function and the formation of durable memory cell populations. In addition, these cells operate in a diverse array of microenvironmental conditions, including the hypoxic regions of solid tumors, healing wounds, and inflamed tissue, placing ...

The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity

“…S-2-Hydroxyglutarate is present in urine of healthy individuals and is elevated in patients with an inborn metabolic disease that results from L2hgdh deficiency [36]. Emerging studies highlight that accumulation of S-2HG can modulate the differentiation of CD8 + T lymphocytes through altering histone and DNA demethylation and thus trigger the immune response [10,37]. The productions of S-2HG are derived from lactate dehydrogenase or malate dehydrogenase and are strongly dependent on HIF-1α signaling [38,39].…”

Metabolic reprogramming and epigenetic modifications on the path to cancer

“…In turn, L2HG stabilizes HIF-1α and modulates the global histone H3K27me3. L2HG induction or supplementation enhances the proliferation, long-term persistence and antitumor capacity of adoptively transferred CD8 + T cells (Tyrakis et al, 2016 ; Cairns and Mak, 2017 ).…”