T cell expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in murine T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that govern T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to control expression of multiple amino acid transporters and that loss of a single Myc-controlled amino acid transporter effectively phenocopies the impact of Myc deletion. This study provides a comprehensive map of how Myc selectively shapes T cell phenotypes, revealing that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs and licences T cell receptor driven proteome reprogramming.
Keywords: Myc; T cell activation; T lymphocyte; amino acid transport; immunology; inflammation; mouse; proteomics.
T cells are white blood cells that form an important part of our immune defence, acting to attack disease-causing microbes and cancer and directing other immune cells to help in this fight. T cells spend most of their time in a resting state, small and inactive, but when an infection strikes, they transform into large, active 'effector' cells. This change involves a dramatic increase in protein production, accompanied by high energy demands. To fully activate, T cells need to boost their metabolism and take in extra amino acids, the building blocks of proteins. For this, they depend upon a protein called Myc. The Myc protein works as a genetic switch, controlling several kinds of cell metabolism, but the molecular details of its effects in T cells remain unclear. Most studies looking to understand Myc have focussed on its role in cancer cells. Here its main job is thought to be driving the use of sugar to make energy. However, it has also been shown to control the levels of transporters that carry amino acids into cells and thus provide the raw materials for protein production. It is possible that Myc plays a similar role in T cells as it does in cancer cells, but this might not be the case because cancer cells have strange biology and do not always accurately represent healthy cells. To find out what role Myc plays in T cell activation, Marchingo et al. compared T cells with and without Myc. The cells lacking Myc were much smaller than their normal counterparts and counts of their proteins revealed why. Without Myc, protein production had stalled. In normal T cells, the number of amino acid transporters increased up to 100 times as cells transformed from a resting to an active state. But, without Myc, this did not happen. The loss of Myc cut off the supply of amino acids, halting protein production. For T cells, the most important amino acid transporter is a protein called System-L transporter Slc7a5. It supplies several essential amino acids, including methionine – the amino acid that starts every single protein. To confirm the role of amino acid transporters in T cell activation, Marchingo et al. deleted the gene for the System-L transporter Slc7a5 directly. This had the same effect as deleting the gene for Myc itself, demonstrating that a key role of Myc in T cell activation is to increase the number of amino acid transporters. Understanding the role of Myc in T cell activation is an important step towards controlling the immune system. At the moment, many research groups are investigating how best to use T cells to fight diseases like cancer. Further analysis of the link between Myc and amino acid transporters could in the future aid the design of such immunotherapies.
© 2020, Marchingo et al.