Publication in detail

Elife. 2015 Oct 23;4. pii: e08698. doi: 10.7554/eLife.08698.

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

Ramiscal, RR; Parish, IA; Lee-Young, RS; Babon, JJ; Blagih, J; Pratama, A; Martin, J; Hawley, N; Cappello, JY; Nieto, PF; Ellyard, JI; Kershaw, NJ; Sweet, RA; Goodnow, CC; Jones, RG; Febbraio, MA; Vinuesa, CG; Athanasopoulos, V

Department of Immunology and Infectious Disease, Australian National University, Canberra, Australia. Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Division of Structural Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, Canada. Immunology Division, Garvan Institute of Medical Research, Sydney, Australia; Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, 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.

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