Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation
- University of Dundee, United Kingdom
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Raw mass spec data files and MaxQuant analysis files for naïve WT, and TCR activated MycWT, MyccKO, Slc7a5WT and Slc7a5cKO T cells are available on the ProteomeXchange data repository (https://www.ebi.ac.uk/pride/archive/login) and can be accessed with identifier PXD016105. Raw mass spec data files and MaxQuant analysis files for OT-1 TCR time-course data are available on the ProteomeXchange data repository (https://www.ebi.ac.uk/pride/archive/login) and can be accessed with identifier PXD016443.
-
OT1 T cell activation time courseProteomeXchange, PXD016443.
-
Single-cell RNA sequencing of OT-I CD8+ T cells after stimulation with different affinity ligandsArrayExpress identifier: E-MTAB-6051.
Article and author information
Author details
Funding
Wellcome (097418/Z/11/Z)
- Doreen A Cantrell
Wellcome (205023/Z/16/Z)
- Doreen A Cantrell
Wellcome (202950/Z/16/Z)
- Doreen A Cantrell
European Molecular Biology Organization (ALTF 1543-2015)
- Julia M Marchingo
European Commission (705984)
- Julia M Marchingo
- Doreen A Cantrell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were performed under Project License PPL 60/4488 and P4BD0CE74. The University of Dundee Welfare and Ethical Use of Animals Committee accepted the project license for submission to the Home Office. Mice were bred and maintained in the WTB/RUTG, University of Dundee in compliance with UK Home Office Animals (Scientific Procedures) Act 1986 guidelines.
Copyright
© 2020, Marchingo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 9,640
- views
-
- 1,281
- downloads
-
- 156
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation
eLife 9:e53725.
https://doi.org/10.7554/eLife.53725
Further reading
-
- Immunology and Inflammation
Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
