title: Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes.
abstract: Myc controls the metabolic reprogramming that supports effector T cell differentiation. The expression of Myc is regulated by the T cell antigen receptor (TCR) and pro-inflammatory cytokines such as interleukin-2 (IL-2). We now show that the TCR is a digital switch for Myc mRNA and protein expression that allows the strength of the antigen stimulus to determine the frequency of T cells that express Myc. IL-2 signalling strength also directs Myc expression but in an analogue process that fine-tunes Myc quantity in individual cells via post-transcriptional control of Myc protein. Fine-tuning Myc matters and is possible as Myc protein has a very short half-life in T cells due to its constant phosphorylation by glycogen synthase kinase 3 (GSK3) and subsequent proteasomal degradation. We show that Myc only accumulates in T cells exhibiting high levels of amino acid uptake allowing T cells to match Myc expression to biosynthetic demands. The combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during immune responses.
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Preston
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Sinclair
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Aneesa
authors.initials: A
authors.lastname: Kaskar
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Jens L
authors.initials: JL
authors.lastname: Hukelmann
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK Instituto Investigación Sanitaria/Hospital Universitario de la Princesa Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Navarro
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland.
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Cowling
authors.affiliation: Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK d.a.cantrell@dundee.ac.uk.
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D003001:Cloning, Molecular; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007376:Interleukin-2 / Q000378:metabolism*; D007976:Leupeptins; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology / Q000378:metabolism*; D011725:Pyridines; D011743:Pyrimidines; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: C473711:Chir 99021; D007376:Interleukin-2; D007976:Leupeptins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Myc; T lymphocytes; TCR signals; cytokine signals; metabolism