1. Cell Biology
  2. Immunology and Inflammation
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Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation

  1. Roybel R Ramiscal  Is a corresponding author
  2. Ian A Parish
  3. Robert S Lee-Young
  4. Jeffrey J Babon
  5. Julianna Blagih
  6. Alvin Pratama
  7. Jaime Martin
  8. Naomi Hawley
  9. Jean Y Cappello
  10. Pablo F Nieto
  11. Julia Ellyard
  12. Nadia J Kershaw
  13. Rebecca A Sweet
  14. Christopher C Goodnow
  15. Russell G Jones
  16. Mark A Febbraio
  17. Carola Vinuesa
  18. Vicki Athanasopoulos
  1. Australian National University, Australia
  2. Baker IDI Heart and Diabetes Institute, Australia
  3. Walter and Eliza Hall Institute of Medical Research, Australia
  4. McGill University, Canada
Research Article
  • Cited 30
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Cite this article as: eLife 2015;4:e08698 doi: 10.7554/eLife.08698

Abstract

T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17 and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17 and Tregs during a T-dependent response, but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of Adenosine Monophosphate-activated Protein Kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN-AMPK metabolic signaling nexus essential for selectively promoting Tfh responses.

Article and author information

Author details

  1. Roybel R Ramiscal

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    For correspondence
    roy.ramiscal@anu.edu.au
    Competing interests
    The authors declare that no competing interests exist.
  2. Ian A Parish

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Robert S Lee-Young

    Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeffrey J Babon

    Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Julianna Blagih

    Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Alvin Pratama

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Jaime Martin

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Naomi Hawley

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean Y Cappello

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Pablo F Nieto

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Julia Ellyard

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Nadia J Kershaw

    Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Rebecca A Sweet

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Christopher C Goodnow

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  15. Russell G Jones

    Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Mark A Febbraio

    Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  17. Carola Vinuesa

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.
  18. Vicki Athanasopoulos

    Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal experiments were approved by the Animal Experimentation Ethics Committee of the Australian National University (Protocols J.IG.71.08 and A2012/05) and the McGill University Ethics Committee (Protocol 7259). Mice were maintained in a specific germ-free environment.

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

Publication history

  1. Received: May 13, 2015
  2. Accepted: October 22, 2015
  3. Accepted Manuscript published: October 23, 2015 (version 1)
  4. Version of Record published: December 31, 2015 (version 2)

Copyright

© 2015, Ramiscal 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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