The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition

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 MALT1 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 MALT1 paracaspase inhibitor, does not prevent the initial phase of T cell activation, in contrast to the pan-protein kinase C inhibitor AEB071. However, MLT-827 strongly impacted survival after activation. We demonstrate this is the consequence of profound inhibition of IL-2 production as well as reduced expression of the high affinity IL-2 receptor (CD25), resulting from defective canonical NF-κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT-827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T cell signaling pathways. Altogether, this first report with a potent and selective MALT1 inhibitor elucidates that MALT1 paracaspase activity indirectly controls gamma-chain receptor dependent signaling, which is required for T cell proliferation and clonal expansion