Transcriptional Regulation of Intestinal Dendritic Cell Subsets

The intestinal immune system is continuously exposed to a myriad of antigenic stimuli. Here, conventional dendritic cells (cDCs) that selectively induce and coordinate effector responses of the immune system are fundamental in maintaining intestinal homeostasis and protective immune defense.
The unmatched ability of cDCs to detect and appropriately respond to a wide range of stimuli is partly due to the extensive heterogeneity that exists within the population. cDCs are broadly classified into two subsets, cDC1s and cDC2s, each exhibiting distinctive developmental dependencies, phenotypes, and functional properties. This subdivision, particularly for cDC2s, has however become increasingly challenging with the uncovering of their variability in transcriptional regulation and phenotypic states. The full range of diversity within intestinal cDCs, and the developmental relationship between cDC1s and cDC2s, are yet to be fully understood.
This work has, therefore, aimed to gain a better understanding of the transcriptional regulation that governs the development, diversification, and functional specialization of intestinal cDC subsets. The studies presented herein specifically focus on the well-known transcription factor antagonists, Bcl6 and Blimp1, whose actions play central roles in differentiating lymphocytes. Notably, Bcl6 and Blimp1 are conserved in cDC1s and cDC2s, respectively, in the murine and human intestines.
In-depth phenotyping and functional studies conducted on transgenic mouse models that lacked either transcription factor revealed that the regulatory roles of Bcl6 and Blimp1 extend beyond lymphocytes and into the myeloid lineage. Our main findings demonstrated a non-redundant role of Bcl6 in determining the identity and relative abundance of cDC subsets in various tissues. In cDCs, Bcl6 suppresses a transcriptional and phenotypical profile associated with cDC2s, while in cDC2s, Bcl6 regulates a distinct subtype that is essential for optimal T_FH and T_H17 cell responses in the spleen and intestine, respectively.
Preliminary findings on Blimp1 showed that deficiency of this transcriptional repressor in cDCs results in a reduction of cDC2s in the small intestine. However, deleting Blimp1 specifically in cDC2s did not lead to any changes in cDC abundance or adaptive responses during steady-state or inflammation and infection of the intestine. Further studies are required to gain a thorough understanding of the role of Blimp1 in cDCs and how it relates to Bcl6 across the myeloid lineage.
Overall, this work has identified Bcl6 as a novel transcription factor in determining cDC subset specification and provided insights into the role of Blimp1 in the intestinal compartment. Understanding the specific developmental and activation requirements that govern intestinal cDC subsets and their function will enhance our ability to harness cDCs for their therapeutic potential of mucosal adaptive immune responses.