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Research Focus

My lab has a long standing interest in the molecular pathogenesis of lymphomas. Based on the functional characterization of recurrent chromosomal translocation in human MALT lymphomas, we identified the long sought-after molecular link that antigen receptors on lymphocytes utilize to activate the transcription factor NF κB. We discovered that the adapter protein BCL10 forms signaling complexes that couple antigen receptor proximal events in T and B cells to canonical NF-κB control. In these settings, BCL10 collaborates with MALT1 and CARD11 to assemble a complex that is essential for adaptive immunity. Loss-of-function mutations lead to immunodeficiency as we have demonstrated and gain-of-function alterations are recurrently observed in various B and also T cell lymphomas. We have also shown that this pathway operates in other immune cell lineages. Moreover, we have discovered that the proteolytic activity of the MALT1 paracaspase is key for the survival of human diffuse large B cell lymphoma (DLBCL) cells, leading to the development of MALT1 inhibitors as anti-lymphoma drugs in academia and industry. We have engineered clinically relevant murine models of human B and T cell lymphoma and utilized these to dissect lymphoma pathogenesis. Using in vivo genetic screens, my group identified the inhibitory receptor PD-1 as a key tumor suppressor in T-cell lymphoma with the respective implications for PD-1 checkpoint inhibition in the clinic.

In addition to the contributions described above, I discovered several signaling pathways in the innate immune cells, which are critical for host defense against fungi, viruses and bacteria, and the regulation of sterile inflammatory responses. In this context, I identified the adapter protein CARD9 as a key regulator of pattern recognition receptor (PRR) signaling and in particular of C-type lectin receptor pathways. Here, CARD9 cooperates with the tyrosine kinase SYK, PKCd and the inflammasomes to create protective pro-inflammatory immune responses. Based on these results, my group identified the first and major human immunodeficiency leading to high susceptibility to fungal infections. In addition, I discovered two intracytoplasmatic nucleic sensing pathways that mediate inflammatory responses upon RNA or DNA virus detection and identified Clec12a as a transmembrane receptor that detects uric acid crystals upon sterile cell death. These findings provided important insights into the regulation of the innate immune system with relevance of immune deficiency research, vaccine development, and understanding of inflammatory diseases. Ongoing work analyses these innate immune pathways in tumor microenvironments.