The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.

T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules1–4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor Programmed Death-1 (PD-1), as a master gene suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.