The role of the transcription factor Bcl6 in classical dendritic cell subsets specification

Dendritic cells are the main antigen-presenting cells of the body and are extremely powerful in mediating immune responses as well as tolerance. It is therefore not surprising that three Nobel Prices in Medicine were awarded to dendritic cell researchers in 2011. Despite their recognized high importance for immune protection as well as homeostasis maintenance, DC biology, subset composition, and developmental requirements are still by far not as well understood as needed. Due to intense research, the immunology community starts to understand better which subsets of DCs instruct T and B cells in various settings with various outcomes. It is becoming more and more obvious that subsets of dendritic cells fulfill different roles in homeostasis and response to immune stimuli, and that external signals affect these subsets differentially.
Dendritic cells express the transcriptional repressor Bcl6, but its role in the development and function has been heavily debated. In my first manuscript and Part 1 of the additional results section of this thesis, we show that despite broad changes in phenotype, the cDC1 and cDC2 lineages are generally maintained in mice lacking Bcl6 within the DC compartment. We found maintained numbers of splenic and LN resident cDC1, but not migratory cDC1 in the mesenteric lymph nodes, suggesting local differences in the impact of Bcl6 deficiency. Although Bcl6-deficiency caused broad changes in gene expression, cDC1 maintained their ability to cross-present. Surprisingly, the absence of Bcl6 in cDC2 caused a complete loss of Notch2-dependent ESAMhi cDC2 in the spleen. Accordingly, DC-targeted Bcl6-deficient mice were unable to mount germinal center responses to blood-derived particulate antigens. Our findings establish Bcl6 as an essential transcription factor for a subset of cDC2 and add to our understanding of the transcriptional landscape underlying cDC2 heterogeneity.
In Part 2 I present some additional results. Mice lacking Bcl6 in cDC1 harbor fewer CD103+ cDC1 in the spleen, which is consistent with a defect in migratory DC populations. Further analysis of global gene expression patterns in splenic cDC1 lacking Bcl6 several putative functional changes, including pathways affecting migration, activation, and cytokine production. Particularly IL-1 and IL-6 gene ontology terms were significantly over-represented in the absence of Bcl6, consistent with enhanced Th1 and Th17 induction mice lacking Bcl6 specifically in cDC1 in vivo. This work will set the stage for future investigations regarding the mechanistic changes governed by Bcl6 within the cDC1 compartment.
Altogether, the studies presented in this thesis systemically examine Bcl6-controlled regulatory networks and provides important insights into Bcl6’s biological functions in DCs.