Roquin Paralogs 1 and 2 Redundantly Repress the Icos and Ox40 Costimulator mRNAs and Control Follicular Helper T Cell Differentiation

SummaryThe Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4+ T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (167 K)Download as PowerPoint slideHighlights► Ox40 is a target of Roquin-1 and Roquin-2 ► In Rc3h1-2-deficient cells the derepression of Ox40 activates NF-κB and Irf4 ► Roquin-1 and Roquin-2 control inappropriate T cell activation and Tfh differentiation ► Combined loss of Rc3h1 and Rc3h2 imposes Tfh differentiation on CD4 T cells