Regulation of T cell homeostasis and activation by MALT1-TRAF6 interaction (A04)

• Subject Area: Immunology
• Term: from 2013 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 210592381

The MALT1 protease activity cleaves signaling mediators, transcriptional regulators and RNA-binding proteins to augment T cell activation, and MALT1 recruits the ubiquitin ligase TRAF6 to activate canonical NF-B signaling. We generated Malt1TBM/TBM mice with destructive mutations in the two TRAF6 binding sites (T6BM1 and T6BM2) of MALT1, which exhibit T cell-driven autoimmunity and autoinflammation. Within this project, we will elucidate how TRAF6 balances MALT1 scaffolding and protease functions in conventional and regulatory T cell subsets. Intriguingly, a human homozygous germline mutation in the T6BM2 leads to a complex immune disorder with signs of immune deficiency and autoimmunity in the affected patient. Thus, we will characterize how tuning of MALT1-TRAF6 interactions by these different mutations modulate T cell activation and immune homeostasis in mice. Contrary to previous assumptions on TRAF6 as a driver of inflammation, our studies will unravel, if TRAF6 inactivating mutations and inhibition may in fact cause autoimmunity and inflammation by unleashing the MALT1 protease.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1054: Control and Plasticity of Cell-Fate Decisions in the Immune System
• Applicant Institution: Ludwig-Maximilians-Universität München
• Project Head: Professor Daniel Krappmann, Ph.D.