Title: Targeting of specific developmental pathways to understand dendritic cell heterogeneity and function
Description: Dendritic cells (DC) are cells of the immune system that are specialized in sensing and responding to pathogens. They coordinate innate and adaptive immune responses to different types of pathogens through the release of inflammatory cytokines, secretion of interferon, and presentation of antigen to naïve T cells. Several different subsets of dendritic cells have been distinguished in the spleen and intestine based on their ability to perform these different functions. However, the specific signaling pathways and transcription factors involved in DC subset differentiation and the precise functions of these subsets are not well understood. Plasmacytoid dendritic cells (PDCs) are a subset of dendritic cells that are specialized at the secretion of type I interferon. Through conditional targeting of E2-2, a transcription factor essential for the specification of the PDC lineage, we have demonstrated a vital role for PDCs in the control of acute and chronic viral infections. In addition, deletion of E2-2 was employed to characterize novel E2-2-dependent, alternative CD8 DC fates.

Furthermore, we have identified a common pathway for the differentiation of the key T cell-priming populations of CD11b DCs in the spleen and intestine. Specific targeting of Notch2 revealed that splenic CD11b DCs are comprised of at least two functionally and developmentally distinct populations that can be distinguished by their expression of the surface molecule Esam. Deletion of Notch2 in dendritic cells also led to the specific loss of CD103CD11b DCs from the lamina propria of the intestine and a corresponding reduction in IL-17-producing T cells. Throughout these studies, the identification of specific developmental pathways of DC subsets has provided key insights into their different functions.