Molecular Analyses of the individual function of the transcriptional Co-Activator BOB.1/OBF.1 in B versus T lymphocytes and its specific contribution to the Germinal Center Reaction

• Applicant: Professorin Dr. Cornelia Brunner
• Subject Area: Immunology ; Cell Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397031396

BOB.1/OBF.1 was originally described as a B cell specific transcriptional co-activator. BOB.1/OBF.1 itself has only very weak affinity to DNA but is recruited by the transcription factors Oct1 and Oct2 to the so called Octamer motif and thereby enhances Octamer-dependent transcription. BOB.1/OBF.1-deficient mice show severe defects at different stages of B cell development, but also in certain T cell populations, like TH1, TH2 or follicular T-helper cells (TFH). The main characteristic of BOB.1/OBF.1-deficient mice is the complete absence of germinal centers and consequently also of germinal center derived B cells, like plasma and memory B cells. However, the question is not fully understood, whether the lack of germinal centers is caused exclusively by the BOB.1/OBF.1 deficiency in B cells or if in addition an inefficient T cell help, provided particularly by TFH, also contributes to this severe phenotype. Because of the lack of appropriate tools to regulate BOB.1/OBF.1 expression in these terminal cell differentiation stages so far we were not able to define the exact impact of BOB.1/OBF.1 to the germinal center reaction by precise molecular analyses. Furthermore, there were only limited options to study BOB.1/OBF.1 deficiency in T cells in the presence of wildtype B cells and vice versa.We have now generated mice bearing floxed BOB.1/OBF.1 alleles. Such a mouse system allows the conditional deletion of BOB.1/OBF.1 expression and therefore the precise analyses of B- as well as T-cell differentiation and function in the absence of the transcriptional co-activator. Using our conditional system together with appropriate Cre expressing mouse lines we are now able to analyze the specific need of BOB.1/OBF.1 expression in early and also in late stages of B-cell development as well as the requirement of BOB.1/OBF.1 for the function of specific T cell subpopulations. A main focus of our project is the identification and further characterization of BOB.1/OBF.1 target genes in order to understand the influence of BOB.1/OBF.1 on B-cell development and function under physiological conditions. Moreover, these analyses allow us to understand how BOB.1/OBF.1 affects germinal center reaction if it is exclusively deleted in defined B and T cell subpopulations. Additionally, due to our newly generated system we are now able to characterize the individual relevance of BOB.1/OBF.1 under immune-pathological conditions and thus to further elucidate the role of BOB.1/OBF.1 in autoimmune processes. Therefore, the aim of the here proposed study is the identification of molecular mechanisms in which the transcriptional co-activator BOB.1/OBF.1 is involved during B and T cell development and differentiation as well as new functions of BOB.1/OBF.1 in those processes under physiological and also immune-pathological conditions.

• DFG Programme: Research Grants