Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes

Gavin C. Preston, Linda V. Sinclair, Aneesa Kaskar, Jens L. Hukelmann, Maria Navarro, Isabel Ferrero, H. Robson MacDonald, Victoria H. Cowling, Doreen A. Cantrell (Lead / Corresponding author)

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2008-2024
Number of pages17
JournalEMBO Journal
Volume34
Issue number15
DOIs
Publication statusPublished - 4 Aug 2015

Fingerprint

Antigen Receptors
T-cells
Interleukin-2
Tuning
T-Lymphocytes
T-Cell Antigen Receptor
Glycogen Synthase Kinase 3
Phosphorylation
Proteins
Half-Life
Cell Differentiation
Switches
Cytokines
Antigens
Amino Acids
Degradation
Messenger RNA
Population

Keywords

  • Cytokine signals
  • Metabolism
  • Myc
  • T lymphocytes
  • TCR signals

Cite this

Preston, Gavin C. ; Sinclair, Linda V. ; Kaskar, Aneesa ; Hukelmann, Jens L. ; Navarro, Maria ; Ferrero, Isabel ; MacDonald, H. Robson ; Cowling, Victoria H. ; Cantrell, Doreen A. / Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. In: EMBO Journal. 2015 ; Vol. 34, No. 15. pp. 2008-2024.
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Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. / Preston, Gavin C.; Sinclair, Linda V.; Kaskar, Aneesa; Hukelmann, Jens L.; Navarro, Maria; Ferrero, Isabel; MacDonald, H. Robson; Cowling, Victoria H.; Cantrell, Doreen A. (Lead / Corresponding author).

In: EMBO Journal, Vol. 34, No. 15, 04.08.2015, p. 2008-2024.

Research output: Contribution to journalArticle

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AU - Ferrero, Isabel

AU - MacDonald, H. Robson

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AU - Cantrell, Doreen A.

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