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NRI AT 20: IMMUNOMETABOLISM

Metabolism as a driver of immunity

Nature Reviews Immunology volume 21, pages 618–619 (2021)Cite this article

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Immune cell activation initiates a programme of cell growth and differentiation, often coupled to proliferation. By the 1970s it was known that lymphocytes engage aerobic glycolysis — that is, they use glucose and produce lactate — to metabolically support their activation process. In the decades that followed, the field of immunology focused on how immune cells receive and deliver signals in order to recognize antigen and orchestrate immune responses. These studies brought molecular definition to the field but largely ignored any role for metabolism. During this same period, cancer biologists were focused on metabolism, as the uncontrolled proliferation of cancer cells suggested targetable metabolic vulnerabilities. A crucial turning point came in the early 2000s when Craig Thompson’s lab established a metabolic parallel, rooted in Warburg metabolism, between the two fields. They highlighted the similarity in the signalling pathways downstream of the insulin receptor and the T cell co-stimulatory receptor CD28, showing that CD28 regulates glucose utilization to support cell growth and energy metabolism (Frauwirth et al., 2002).

This work reinforced the idea that immunologists needed to take note of metabolism. This was particularly important as new technologies opened the door to the collection of large datasets from unbiased genome-wide transcriptional profiling and metabolite analyses. Key foundational findings that emerged were that memory CD8+ T cells preferentially use catabolic pathways, like fatty acid oxidation, to generate energy and, critically, the pharmacological manipulation of energy metabolism in these cells promotes memory T cell generation and immunity to cancer (Pearce et al., 2009). Furthermore, MYC was shown to control metabolic reprogramming in activated T cells, highlighting that transcriptional remodelling underlies the robustness of metabolic changes after activation (Wang et al., 2011). Other important work showed that distinct CD4+ T cell subsets use different metabolic pathways to support their function, with T helper 1 (TH1), TH2 and TH17 cells engaging glycolysis and regulatory T cells preferring fatty acid oxidation (Michalek et al., 2011). In parallel, the importance of cell-intrinsic changes in metabolism for innate immunity became apparent when Toll-like receptor agonists were shown to stimulate a metabolic transition to glycolysis in dendritic cells, with activation-associated functions again linked to metabolic state (Krawczyk et al., 2010). These reports laid the groundwork for the field of ‘immunometabolism’, which has grown explosively in the past decade.

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References

Original articles

  • Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002)

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  • Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010)

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  1. Johns Hopkins University, Baltimore, MD, USA

    Erika L. Pearce

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  1. Erika L. Pearce
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Correspondence to Erika L. Pearce.

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The author is a SAB member of ImmunoMet and a Founder of Rheos Medicines.

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Pearce, E.L. Metabolism as a driver of immunity. Nat Rev Immunol 21, 618–619 (2021). https://doi.org/10.1038/s41577-021-00601-3

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