RelB as a master regulator of the thymic medulla: characterization of factors that control RelB expression and the role of the RelB target gene Enpp2/Atx

• Applicant: Professor Dr. Christoph Englert, since 11/2014
• Subject Area: Cell Biology ; Immunology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 154810081

In the previous funding period, we showed that mice with a thymic epithelial cell (TEC)-specific ablation of the NF-kB family member RelB (RelbTEC-KO) lacked all medullary mTECs resulting in autoimmunity. Surprisingly, the RelbTEC-KO autoimmune pathology was very mild compared to Relb-null mice with respect to both severity of inflammatory infiltrates and number of affected organs. Notably, RelaTEC-KO mice had only a partial loss of mTECs and did not develop autoimmunity. Rescue experiments showed that the RelaTEC-KO phenotype was largely due to decreased expression of RelB, which regulated mTEC numbers in a dose-dependent manner. Our results indicate that RelB drives commitment of bipotent TEC precursors to the mTEC lineage.To investigate whether other components of the classical NF-kB signaling pathway regulate RelB levels in mTECs we will initially focus on c-Rel, which cooperates in vitro with RelA in the induction of RelB expression. In addition, we will investigate whether the TNF receptor-associated factor TRAF6 is upstream of RelB. The role of RelB in early mTEC development will be addressed using the newly generated Relb-Cre-P2A-Katushka reporter mouse line. These mice enable us to purify RelB-positive and RelB-negative mTECs by flow cytometry for transcriptome analyses and the identification of novel RelB target genes. Since the severity of autoimmunity correlated with markedly increased atrophy of the thymic medulla in RelB-null compared to RelbTEC-KO mice, we will furthermore investigate the role of RelB in development and function of non-TECs, such as mesenchymal and endothelial cells. In particular, we want to find out the cellular origin and function of the secreted enzyme autotaxin, which is expressed in the thymus by non-TECs in a RelB-dependent manner.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Falk Weih, until 11/2014 (†)