Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote [T.sub.H]17 differentiation

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (TFH cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the [T.sub.H]17 subset of helper T cells in the lungs. Roquin inhibited [T.sub.H]17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the [T.sub.H]17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IkBNS and Ik Be This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance [T.sub.H]17 differentiation.