Cell 153:1036-1049 2013/05/23

Regnase-1, also known as Zc3h12a, is an RNase protein that destabilizes a set of mRNAs such as Il6 and Il12b via their 3’ UTRs. Deletion of Regnase-1 causes a severe autoimmune disease characterized by accumulation of effector/memory T cells and plasma cells and hyperimmunoglobulinemia in mice. However, the mechanism of Regnase-1-mediated immune regulation is still unclear. Deletion of Il6 or Il12p40 did not rescue the disease of Regnase-1-deficient mice. Here we show that Regnase-1 is essential for preventing aberrant effector CD4 T cell generation cell-autonomously. T cell-specific deletion of Regnase-1 led to development of an autoimmune disease. Moreover, although Regnase-1 regulates a set of mRNAs in T cells including c-Rel, we found that c-Rel is involved in development of the disease in Regnase-1-deficient mice. Notably, Regnase-1 is constitutively expressed and is cleaved by Malt1 in a manner dependent on TCR stimulation. Furthermore, Malt1-mediated cleavage of Regnase-1 induces stabilization of its target mRNAs, thereby controlling T cell activation post-transcriptionally. Collectively, these results demonstrate that dynamic control of Regnase-1 expression in T cells is critical for regulating T cell activation.