Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation

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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.

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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.
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.
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.
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.
Julianna Blagih

Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, Canada

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The authors declare that no competing interests exist.
Alvin Pratama

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
Jaime Martin

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
Naomi Hawley

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
Jean Y Cappello

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
Pablo F Nieto

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
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.
Nadia J Kershaw

Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

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The authors declare that no competing interests exist.
Rebecca A Sweet

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia

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The authors declare that no competing interests exist.
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.
Russell G Jones

Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, Canada

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.

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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.