MicroRNA-146a regulates ​ICOS–​ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres

Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that ​microRNA-146a (​miR-146a) is highly expressed in Tfh cells and peak ​miR-146a expression marks the decline of the Tfh response after immunization. Loss of ​miR-146a causes cell-intrinsic accumulation of Tfh and GC B cells. ​MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ​ICOS is the most strongly cell autonomously upregulated target in ​miR-146a-deficient T cells. In addition, ​miR-146a deficiency leads to increased ​ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ​ICOS signalling, either by injections of low dose of ​ICOSL blocking antibody or by halving the gene dose of ​Icos in ​miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, ​miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses