Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation
Roybel R Ramiscal,
Ian A Parish,
Robert S Lee-Young,
Jeffrey J Babon,
Julianna Blagih,
Alvin Pratama,
Jaime Martin,
Naomi Hawley,
Jean Y Cappello,
Pablo F Nieto,
Julia I Ellyard,
Nadia J Kershaw,
Rebecca A Sweet,
Christopher C Goodnow,
Russell G Jones,
Mark A Febbraio,
Carola G Vinuesa,
Vicki Athanasopoulos
Affiliations
Roybel R Ramiscal
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Ian A Parish
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Robert S Lee-Young
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
Jeffrey J Babon
Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Julianna Blagih
Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, Canada
Alvin Pratama
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Jaime Martin
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Naomi Hawley
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Jean Y Cappello
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Pablo F Nieto
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Julia I Ellyard
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Nadia J Kershaw
Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Rebecca A Sweet
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Christopher C Goodnow
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia; Immunology Division, Garvan Institute of Medical Research, Sydney, Australia
Russell G Jones
Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, Canada
Mark A Febbraio
Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia
Carola G Vinuesa
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
Vicki Athanasopoulos
Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australia
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.
