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

Roybel R Ramiscal,Alvin Pratama,Russell G Jones,Jaime Martin,Nadia J Kershaw,Jeffrey J Babon,Pablo F Nieto,Jean Y Cappello,Ian A Parish,Carola G Vinuesa,Naomi Hawley,Christopher C Goodnow,Julianna Blagih,Julia I Ellyard,Rebecca A Sweet,Mark A Febbraio,Robert S Lee-Young,Vicki Athanasopoulos

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.

Highlights

High-affinity and long-lasting humoral immunity against infection requires controlled cross-talk between limiting CD4+CXCR5highPD1highBCL6high T follicular helper (Tfh) cells and immunoglobulinmaturing germinal center (GC) B cells in secondary lymphoid tissues (King et al, 2008; Victora and Nussenzweig, 2012; Nutt and Tarlinton, 2011; Ramiscal and Vinuesa, 2013)
ROQUIN RING-deficient T cells were inefficient in supporting GC formation (Figure 1e, f and Figure 1—figure supplement 3b), which was associated with reduced IL-21 production (Figure 2a), a T follicular helper cells (Tfh) signature cytokine vital in supporting GC reactions (Liu and King, 2013)
We show at the molecular level, that the RING domain of ROQUIN is required to attenuate AMPK signals

Summary

Introduction

High-affinity and long-lasting humoral immunity against infection requires controlled cross-talk between limiting CD4+CXCR5highPD1highBCL6high T follicular helper (Tfh) cells and immunoglobulinmaturing germinal center (GC) B cells in secondary lymphoid tissues (King et al, 2008; Victora and Nussenzweig, 2012; Nutt and Tarlinton, 2011; Ramiscal and Vinuesa, 2013). Deregulation of Tfh cells can lead to faulty GC selection that may seed the production of autoantibodies (Weinstein et al, 2012; Vinuesa et al, 2005; Kim et al, 2015; Linterman et al, 2009) and GCderived malignancies such as follicular lymphoma Cell biology Immunology eLife digest The immune system protects the body from invading microbes like bacteria and viruses. Upon recognizing the presence of these microbes, cells in the immune system are activated to destroy the foreign threat and clear it from the body

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Results

Conclusion