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Hurry up and wait, then activate and translate!

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Science Immunology  04 Jan 2019:
Vol. 4, Issue 31, eaaw4888
DOI: 10.1126/sciimmunol.aaw4888

Abstract

The immunometabolic pivot from reliance on fatty acid oxidation to glycolysis during T cell activation is, in part, reliant on the regulation of translation of key metabolic enzymes.

Naïve and activated T CD4 T cells have quite different tastes in energy sources. Naïve CD4 T cells churn along, powered by fatty acid oxidation and using an overall catabolic strategy. Activated CD4 T cells have different goals, needing to generate many progeny to address their activating stimuli. Therefore, activated CD4 T cells switch to an anabolic strategy and power themselves and their progeny with a more sugary (glycolytic) fuel source. However, it remained unclear how naïve CD4 T cells pivot quickly from one metabolic state to another, and this is the focus of this work.

Ricciardi et al. used available datasets to compare the relative abundance of transcripts versus translated proteins for individual genes. A small subset of genes were present in naïve CD4 T cells with reasonable messenger RNA (mRNA) levels but without protein. These included two key metabolic enzymes, acetyl-CoA carboxylase (ACC1) and glucose transporter 1(GLUT1). One might expect this could be due, in part, to reduced translational machinery in naïve T cells (thus leading mRNA to accumulate). Instead, naïve CD4 T cells were found to have equivalent or elevated levels of core components of translation. However, there was evidence of inhibition of translation initiation. So, naïve CD4 T cells had sufficient mRNA to translate and ribosomes ready to translate, but no signal to start the process, leaving naïve CD4 T cells in limbo. Upon T cell receptor stimulation, ACC1 and GLUT1 mRNAs were recruited to join polysomes and initiate translation. Pharmacological inhibition of transcription versus translation demonstrated that the increase in ACC1 and GLUT1 upon T cell activation was predominantly dependent on translation. They identified the assembly of the eukaryotic translation initiation complex 4F complex as key for translation initiation in this setting.

This paper adds an additional layer of complexity to the immunometabolic pivot between naïve and activated CD4 T cells, highlighting a role for the regulation of translation of metabolic enzymes. Although this will require additional mechanistic studies in naïve CD4 T cells and broadened testing in additional human T cell subsets, it may lead to new targets for immunometabolic intervention in human disease, either adjunctively or even as primary therapy.

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