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 a-ketoglutarate (a-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.

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