Now, Amelie Köhler from the Mucosal Immunology group at ZAUM was able to identify a novel ‘brake’ for these ROR(gt)+ Tregs. Together with colleagues from the University of Mainz Amelie Köhler was able to show that mice with a genetic deficiency of the atypical NF-kB family member Bcl3 displayed elevated frequencies and cell numbers of Tregs and specifically ROR(gt)+ Tregs. Mice that overexpressed Bcl3 showed the opposite phenotype. By various approaches the team was also able to show that this effect was based on a cell-intrinsic effect due to dysregulation of several pathways associated to Treg differentiation. “This result was rather surprising as most gene knockouts typically result in a failure of T- or Treg cell differentiation and only rarely in an expansion,” describes PD Dr. Caspar Ohnmacht the results who led the study. Importantly, the Bcl3-deficient Tregs were still functional and able to suppress colitis. But why is the number of these cells limited by Bcl3 at all? “The immune system needs to enable effective immune responses while at the same time tolerizing harmless antigens,” explains Caspar Ohnmacht. The identification of such regulatory molecular nodes will help to develop novel therapeutic strategies for patients with diseases associated with intestinal loss-of-tolerance such as Ulcerative Colitis or food allergy.
The exact molecular target of Bcl3, the stability of Bcl3-deficient Tregs over time and other interesting aspect will be further investigated by the team together with Dr. Nadine Hoevelmeyer (University of Mainz) in the frame of the DFG-funded Transregio TRR355 (https://trr355.uni-mainz.de).