Antigen receptor control of methionine metabolism in T cells

  1. Linda V Sinclair  Is a corresponding author
  2. Andrew JM Howden
  3. Alejandro Brenes
  4. Laura Spinelli
  5. Jens L Hukelmann
  6. Andrew N Macintyre
  7. Xiaojing Liu
  8. Sarah Thomson
  9. Peter M Taylor
  10. Jeffrey C Rathmell
  11. Jason W Locasale
  12. Angus I Lamond
  13. Doreen A Cantrell  Is a corresponding author
  1. University of Dundee, United Kingdom
  2. Vanderbilt University, United States
  3. Duke University, United States
  4. Vanderbilt Universit, United States

Abstract

Immune activated T lymphocytes modulate the activity of key metabolic pathways to support the transcriptional reprograming and reshaping of cell proteomes that permits effector T cell differentiation. The present study uses high resolution mass spectrometry and metabolic labelling to explore how murine T cells control the methionine cycle to produce methyl donors for protein and nucleotide methylations. We show that antigen receptor engagement controls flux through the methionine cycle and RNA and histone methylations. We establish that the main rate limiting step for protein synthesis and the methionine cycle is control of methionine transporter expression. Only T cells that respond to antigen to upregulate and sustain methionine transport are supplied with methyl donors that permit the dynamic nucleotide methylations and epigenetic reprogramming that drives T cell differentiation. These data highlight how the regulation of methionine transport licenses use of methionine for multiple fundamental processes that drive T lymphocyte proliferation and differentiation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files, or being submitted to the PRIDE ProteomeXchange consortium.

The following data sets were generated

Article and author information

Author details

  1. Linda V Sinclair

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    For correspondence
    l.v.sinclair@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1248-7189
  2. Andrew JM Howden

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Alejandro Brenes

    Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8298-2463
  4. Laura Spinelli

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Jens L Hukelmann

    Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrew N Macintyre

    Center for Immunobiology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaojing Liu

    Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sarah Thomson

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter M Taylor

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Jeffrey C Rathmell

    Center for Immunobiology, Vanderbilt Universit, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jason W Locasale

    Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7766-3502
  12. Angus I Lamond

    Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6204-6045
  13. Doreen A Cantrell

    Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom
    For correspondence
    d.a.cantrell@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7525-3350

Funding

Wellcome (097418/Z/11/Z)

  • Doreen A Cantrell

Wellcome (202950/Z/16/Z)

  • Doreen A Cantrell

Wellcome (205023/Z/16/Z)

  • Doreen A Cantrell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. This work was supported by the Wellcome Trust (Principal Research Fellowship to D.A.C. 097418/Z/11/Z and 205023/Z/16/Z ; Wellcome Trust Equipment Award 202950/Z/16/Z ).

Reviewing Editor

  1. Ronald N Germain, National Institute of Allergy and Infectious Diseases, United States

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 licence for submission to the HO. All studies, breeding and maintenance performed in Dundee in compliance with UK Home Office Animals (Scientific Procedures) Act 1986 guidelines. Individual study plans were approved and deemed compliant by the UVS/Named Compliance Officer.

Version history

  1. Received: December 6, 2018
  2. Accepted: March 26, 2019
  3. Accepted Manuscript published: March 27, 2019 (version 1)
  4. Version of Record published: May 2, 2019 (version 2)

Copyright

© 2019, Sinclair 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.

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  1. Linda V Sinclair
  2. Andrew JM Howden
  3. Alejandro Brenes
  4. Laura Spinelli
  5. Jens L Hukelmann
  6. Andrew N Macintyre
  7. Xiaojing Liu
  8. Sarah Thomson
  9. Peter M Taylor
  10. Jeffrey C Rathmell
  11. Jason W Locasale
  12. Angus I Lamond
  13. Doreen A Cantrell
(2019)
Antigen receptor control of methionine metabolism in T cells
eLife 8:e44210.
https://doi.org/10.7554/eLife.44210

Share this article

https://doi.org/10.7554/eLife.44210

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