Project A04 -Regulation of T cell homeostasis and activation by MALT1-TRAF6 interaction
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.