The T‐cell fingerprint of MALT 1 paracaspase revealed by selective inhibition

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT 1 proteolytic function regulates T‐cell activation and fate after engagement of the T‐cell receptor pathway. We show that MLT ‐827, a potent and selective MALT 1 paracaspase inhibitor, does not prevent the initial phase of T‐cell activation, in contrast to the pan‐protein kinase C inhibitor AEB 071. However, MLT ‐827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL ‐2 production as well as reduced expression of the IL ‐2 receptor alpha subunit ( CD 25), resulting from defective canonical NF ‐κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT ‐827 revealed a unique transcriptional fingerprint of MALT 1 protease activity, providing evidence for broad control of T‐cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT 1 paracaspase activity integrates several T‐cell activation pathways and indirectly controls gamma‐chain receptor dependent survival, to impact on T‐cell expansion.