Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system l-amino acid transport is blocked. We identify SLC7A5 as the predominant system l-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function.

Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate-malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate-malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.

Natural killer (NK) cells are lymphocytes with important roles for innate and adaptive immune responses to tumours and viral infection. However, in certain chronic diseases, including obesity and cancer, NK cells are found to have impaired functional responses. Recently research has highlighted the importance of NK cell metabolism in facilitating robust NK cell effector functions. This article will discuss our current understanding of murine and human NK cell metabolism and the key signalling pathways that mediate metabolic responses in NK cells.Furthermore, it will explore how defects in metabolism can contribute to the generation of dysfunctional NK cells in chronic disease. Finally, the potential for new therapeutic strategies targeting cellular metabolism will be discussed.

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Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Metabolic dysfunction is linked to defective NK cell responses in diseases such as obesity and cancer. The transcription factors, sterol regulatory element binding protein (SREBP) and cMyc, are crucial for controlling NK cell metabolic and functional responses, though the mechanisms involved are not fully understood. This study reveals a new role for SREBP in NK cells in supporting de novo polyamine synthesis through facilitating elevated cMyc expression. Polyamines have diverse roles and their de novo synthesis is required for NK cell glycolytic and oxidative metabolism and to support optimal NK cell effector functions. When NK cells with impaired SREBP activity were supplemented with exogenous polyamines, NK cell metabolic defects were not rescued but these NK cells displayed significant improvement in some effector functions. One role for polyamines is in the control of protein translation where spermidine supports the posttranslational hypusination of translation factor eIF5a. Pharmacological inhibition of hypusination also impacts upon NK cell metabolism and effector function. Considering recent evidence that cholesterol‐rich tumor microenvironments inhibit SREBP activation and drive lymphocyte dysfunction, this study provides key mechanistic insight into this tumor‐evasion strategy.

1. Effective wildlife restoration is a critical requirement of many conservation actions. The outcome of conservation interventions can be optimized through knowledge of species' habitat requirements, but few studies consider the impact of using explicit evidence from dedicated local research to inform the design phase of habitat management. Furthermore, interventions administered externally from the top down, whilst simpler than those developed in discussion with multiple stakeholders including land managers (i.e. co-development), run the risk of failing to engage local people. 2. In this study, we focus on interventions in the Scottish Highlands to improve the availability and suitability of breeding ponds for local amphibian assemblages. We collected and analysed data based on 129 ecological variables across 88 reference ponds to quantify the local habitat preferences. We used the findings from these analyses to inform the construction or restoration of 25 intervention ponds co-developed in partnership with stakeholders (landowners, foresters, citizen scientists and government agencies). Following the interventions, we monitored amphibian communities at these sites over 4 years. We assessed presence and abundance of all five native amphibians (the anurans Rana temporaria and Bufo bufo, and the salamanders Lissotriton helveticus, L. vulgaris and Triturus cristatus) using egg searching, dip-netting, torching and trapping. 3. The new habitats were overall characterized by ecological conditions more favourable to amphibians than the reference ponds. We recorded a total of 51 colonization events. Within two breeding seasons after construction or restoration, the intervention ponds hosted the full complement of species, mirroring amphibian diversity patterns found in the local reference ponds. 4. Our study shows that ecological research to quantify local habitat requirements and working with commercial landmanagers to ensure equitable benefits prior to designing conservation actions can promote rapid and efficient recovery of wildlife.

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