The role of c-Rel and IkappaBNS in T-cell activation and the differentiation of follicular T cells

• Applicant: Professor Dr. Ingo Schmitz
• Subject Area: Immunology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268984183

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) is a paradigm of an inducible transcription factor. It is kept inactive in the cytoplasm by inhibitor of kB (IkB) proteins. These proteins bind to NF-kB via their ankyrin repeats masking the nuclear localization sequence of NF-kB thus sequestering NF-kB away from its target DNA binding sites. However, next to these cytosolic proteins another class of IkB proteins exists that is localized to the nucleus and modulates the transcriptional activity of NF-kB by yet not well-defined mechanisms. Nevertheless, it is clear that nuclear (or atypical) IkB proteins convey specificity towards the set of genes targeted by NF-kB.IkBNS is one of these atypical IkB proteins and we demonstrated that it is crucial for the development of regulatory T (Treg) cells since it directly induces expression of Foxp3, the Treg specifying master transcription factor. Together with the NF-kB subunit c-Rel, IkBNS is essential for Treg development because double knockout mice basically lack Treg cells and we showed that these two NF-kB factors regulate both developmental routes, i.e. via CD25+Foxp3- and CD25-Foxp3+ precursors. Furthermore, we were able to define a CD122 expressing pre-precursor stage of Treg development. Surprisingly, c-Rel-IkBNS double-deficient mice did not show any signs of autoimmunity, even at the age of about 1 year. This implies that both NF-kB factors are essential for the activation of effector T cells. Indeed, we demonstrated that IkBNS is crucial for the differentiation of Th1 and Th17 cells. We want to continue these investigations and decipher how IkBNS and c-Rel govern T cell activation. To this end, we will analyze signaling cascades downstream of the TCR (e.g. MAPK, mTOR) and cell death. Moreover, gene expression profiling will identify common and selective target genes of c-Rel and IkBNS. Selected targets will be functionally characterized.Another T cell subset that differentiates upon strong TCR signals (as e.g. Treg cells) is the follicular T (Tfh) cell subset. These Tfh cells are providing essential help to B cells in the germinal center reaction giving rise to high affinity antibodies that mediate long-lasting protection towards infections. Our preliminary data show that IkBNS is highly expressed in Tfh cells. However, in contrast to published data that IkBNS is crucial for Tfh differentiation in a vaccination model, we detected normal frequencies of Tfh cells in Peyer’s patches of IkBNS-deficient animals. Thus, acute and chronic stimuli of Tfh differentiation may have a differential requirement for IkBNS. We want to elucidate these requirements in conditional knockout models of IkBNS in chronic (Peyer’s patches) and acute (vaccination; influenza A virus infection) situations.

• DFG Programme: Research Grants