Dendritic Cell Development and Function
Conventional dendritic cells (cDCs) are versatile controllers of the immune system that sense pathogens and damage to initiate the bodies defense. They exist as developmentally distinct subsets with unique functions in immunity. Yet, the signals that drive cDC differentiation and adaptation to different tissue niches remain poorly defined.
cDCs are short lived and constantly replenished from bone marrow progenitors. We hypothesize that the cellular identity of cDCs is first imprinted by developmental origin (nature) and want to understand how it can be shaped environmental factors (nurture), such as the tissue microenvironment. We aim to identify cell intrinsic and extrinsic signals that drive the terminal differentiation of cDCs to establish tissue specific sentinel networks. We address our scientific questions in part using mouse models that allow for lineage tracing and visualization of dendritic cells based on their ontogenetic descendence from committed precursors, coupled to single cell technologies, transcriptomics and innovative imaging techniques. The tissue specific functions of dendritic cell subsets in immunity are further studied by depleting these cells and assessing subsequent immune responses.
Early immune balance is essential for survival and the establishment of healthy immunity in later life. cDCs in neonates are qualitatively distinct from those in adults. We have shown that in early life cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves18. Surprisingly, developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. Based on these and other observations, we postulate that cDC1 and cDC2 adapt their functions in response to environmental cues to meet age-specific immunological needs, ensure survival and immune homeostasis. Accordingly, we are currently investigating how cDC function adopts to immune challenges that occur in early life, such as the sudden encounter with microbes at birth, or the transition from breast feeding to solid foods in suckling neonates.
While cDC are the most potent APCs, RORgt-expressing APCs have recently been identified as a distinct group of heterogeneous tissue-resident APCs that can regulate inflammation and enforce tolerance to self and commensals. In line, we have recently discovered cDC2-like cells in murine spleen that express RORgt but do not arise from myeloid cDC progenitors. These cells are transcriptionally more similar to cDC2 than RORgt-expressing innate lymphocytes (ILC3s). We currently aim to better characterize these RORgt-expressing DC like cells by investigating their phenotypic, functional, and transcriptional relatedness to other APCs and by defining their unique functions in immunity. These studies will provide insight into the division of labor between APC subtypes in different tissues.
The major challenges in the design of future therapies are to target specific components of the immune response in the absence of general immunosuppression. We think that understanding the unique functions of dendritic cells in the context of their microenvironment will help determine their potential to be targeted in immunotherapy. A better understanding of the development of dendritic cells may also help us identify factors that can be used to manipulate dendritic cell differentiation and function in vaccines or therapeutic settings.